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Yeshna, Singh M, Monika, Kumar A, Garg V, Jhawat V. Pathophysiology and emerging therapeutic strategies for cervical spondylosis: The role of pro-inflammatory mediators, kinase inhibitors, and Organogel based drug delivery systems. Int Immunopharmacol 2025; 151:114350. [PMID: 40010157 DOI: 10.1016/j.intimp.2025.114350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/20/2025] [Accepted: 02/20/2025] [Indexed: 02/28/2025]
Abstract
Cervical spondylosis is a prevalent ailment characterized by chronic wear and degenerative changes affecting the cervical spine, leading to various clinical syndromes such as axial neck pain, cervical myelopathy, and cervical radiculopathy. The pathophysiology of the development of cervical alterations is multifaceted, with alterations in the normal physiology and pathogenesis of intervertebral disc degeneration. The involvement of pro-inflammatory mediators, such as interleukin-1, tumor necrosis factor-α, interleukin-4, interleukin-6, and interleukin-10, in the pathological processes associated with intervertebral disc degeneration offers potential therapeutic targets. The review also introduces kinase inhibitors as potential treatments for cervical spondylosis. Protein kinase inhibitors, including mitogen-activated protein kinase (MAPK), Janus kinase (JAK), and spleen tyrosine kinase (SYK), are explored for their anti-inflammatory properties. The article discusses their potential in modulating inflammatory signaling cascades and presents them as attractive candidates for treating immune-mediated disorders. Inhibitors of Nuclear Factor-κB, p38 MAPK, Jun-N terminal kinase (JNK), and Extracellular signal-regulated kinase (ERK) have shown efficacy in suppressing inflammatory responses, offering potential avenues for intervention in this prevalent condition. Organogels are semi-solid materials formed by trapping an organic solvent within a three-dimensional cross-linked network. They hold considerable potential in drug delivery, especially in enhancing drug solubility, facilitating controlled release, and improving skin penetration. These properties of organogels can help treat or alleviate the symptoms of cervical spondylosis.
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Affiliation(s)
- Yeshna
- Department of Pharmaceutical Science, School of Healthcare and Allied Science, GD Goenka University, Gurugram, Haryana, India
| | - Monika Singh
- Department of Pharmaceutical Science, School of Healthcare and Allied Science, GD Goenka University, Gurugram, Haryana, India
| | - Monika
- Department of Pharmaceutical Science, School of Healthcare and Allied Science, GD Goenka University, Gurugram, Haryana, India
| | - Ashok Kumar
- Faculty of Pharmacy, Kalinga University, Naya Raipur, Chhattisgarh, India
| | - Vandana Garg
- Department of Pharmaceutical Science, MD University, Rohtak, India
| | - Vikas Jhawat
- Department of Pharmaceutical Science, School of Healthcare and Allied Science, GD Goenka University, Gurugram, Haryana, India.
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Vu QV, Sayama S, Ando M, Kataoka T. Sesquiterpene Lactones Containing an α-Methylene-γ-Lactone Moiety Selectively Down-Regulate the Expression of Tumor Necrosis Factor Receptor 1 by Promoting Its Ectodomain Shedding in Human Lung Adenocarcinoma A549 Cells. Molecules 2024; 29:1866. [PMID: 38675685 PMCID: PMC11053566 DOI: 10.3390/molecules29081866] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/16/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Alantolactone is a eudesmane-type sesquiterpene lactone containing an α-methylene-γ-lactone moiety. Previous studies showed that alantolactone inhibits the nuclear factor κB (NF-κB) signaling pathway by targeting the inhibitor of NF-κB (IκB) kinase. However, in the present study, we demonstrated that alantolactone selectively down-regulated the expression of tumor necrosis factor (TNF) receptor 1 (TNF-R1) in human lung adenocarcinoma A549 cells. Alantolactone did not affect the expression of three adaptor proteins recruited to TNF-R1. The down-regulation of TNF-R1 expression by alantolactone was suppressed by an inhibitor of TNF-α-converting enzyme. Alantolactone increased the soluble forms of TNF-R1 that were released into the culture medium as an ectodomain. The structure-activity relationship of eight eudesmane derivatives revealed that an α-methylene-γ-lactone moiety was needed to promote TNF-R1 ectodomain shedding. In addition, parthenolide and costunolide, two sesquiterpene lactones with an α-methylene-γ-lactone moiety, increased the amount of soluble TNF-R1. Therefore, the present results demonstrate that sesquiterpene lactones with an α-methylene-γ-lactone moiety can down-regulate the expression of TNF-R1 by promoting its ectodomain shedding in A549 cells.
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Affiliation(s)
- Quy Van Vu
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
| | - Shinsei Sayama
- Department of Natural Sciences (Chemistry), Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan;
| | - Masayoshi Ando
- Department of Chemistry and Chemical Engineering, Niigata University, 2-8050 Ikarashi, Nishi-ku, Niigata 950-2181, Japan
| | - Takao Kataoka
- Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
- Biomedical Research Center, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
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Saad MI, Jenkins BJ. The protease ADAM17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond. FEBS J 2024; 291:10-24. [PMID: 37540030 DOI: 10.1111/febs.16923] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/04/2023] [Accepted: 08/02/2023] [Indexed: 08/05/2023]
Abstract
The protease A Disintegrin And Metalloproteinase 17 (ADAM17) plays a central role in the pathophysiology of several diseases. ADAM17 is involved in the cleavage and shedding of at least 80 known membrane-tethered proteins, which subsequently modulate several intracellular signaling pathways, and therefore alter cell behavior. Dysregulated expression and/or activation of ADAM17 has been linked to a wide range of autoimmune and inflammatory diseases, cancer, and cardiovascular disease. In this review, we provide an overview of the current state of knowledge from preclinical models and clinical data on the diverse pathophysiological roles of ADAM17, and discuss the mechanisms underlying ADAM17-mediated protein shedding and the potential therapeutic implications of targeting ADAM17 in these diseases.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., Australia
- South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, SA, Australia
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Schumacher N, Thomsen I, Brundert F, Hejret V, Düsterhöft S, Tichý B, Schmidt-Arras D, Voss M, Rose-John S. EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119489. [PMID: 37271223 DOI: 10.1016/j.bbamcr.2023.119489] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 04/14/2023] [Accepted: 05/05/2023] [Indexed: 06/06/2023]
Abstract
The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFR-downstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer.
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Affiliation(s)
- Neele Schumacher
- Institute of Biochemistry, Medical Faculty, Kiel University, Germany.
| | - Ilka Thomsen
- Institute of Biochemistry, Medical Faculty, Kiel University, Germany
| | - Florian Brundert
- Institute of Biochemistry, Medical Faculty, Kiel University, Germany
| | - Vaclav Hejret
- CEITEC-Central European Institute of Technology, Masaryk University, Czech Republic
| | - Stefan Düsterhöft
- Institute of Molecular Pharmacology, University Hospital Aachen/RWTH, Aachen, Germany
| | - Boris Tichý
- CEITEC-Central European Institute of Technology, Masaryk University, Czech Republic
| | | | - Matthias Voss
- Institute of Biochemistry, Medical Faculty, Kiel University, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Medical Faculty, Kiel University, Germany
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5
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A Bioengineering Strategy to Control ADAM10 Activity in Living Cells. Int J Mol Sci 2023; 24:ijms24020917. [PMID: 36674432 PMCID: PMC9863580 DOI: 10.3390/ijms24020917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/30/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
A Disintegrin and Metalloprotease 10, also known as ADAM10, is a cell surface protease ubiquitously expressed in mammalian cells where it cuts several membrane proteins implicated in multiple physiological processes. The dysregulation of ADAM10 expression and function has been implicated in pathological conditions, including Alzheimer's disease (AD). Although it has been suggested that ADAM10 is expressed as a zymogen and the removal of the prodomain results in its activation, other potential mechanisms for the ADAM10 proteolytic function and activation remain unclear. Another suggested mechanism is post-translational modification of the cytoplasmic domain, which regulates ADAM10-dependent protein ectodomain shedding. Therefore, the precise and temporal activation of ADAM10 is highly desirable to reveal the fine details of ADAM10-mediated cleavage mechanisms and protease-dependent therapeutic applications. Here, we present a strategy to control prodomain and cytosolic tail cleavage to regulate ADAM10 shedding activity without the intervention of small endogenous molecule signaling pathways. We generated a series of engineered ADAM10 analogs containing Tobacco Etch Virus protease (TEV) cleavage site (TEVcs), rendering ADAM10 cleavable by TEV. This strategy revealed that, in the absence of other stimuli, the TEV-mediated removal of the prodomain could not activate ADAM10. However, the TEV-mediated cleavage of the cytosolic domain significantly increased ADAM10 activity. Then, we generated ADAM10 with a minimal constitutively catalytic activity that increased significantly in the presence of TEV or after activating a chemically activatable TEV. Our results revealed a bioengineering strategy for controlling the ADAM10 activity in living cells, paving the way to obtain spatiotemporal control of ADAM10. Finally, we proved that our approach of controlling ADAM10 promoted α-secretase activity and the non-amyloidogenic cleavage of amyloid-β precursor protein (APP), thereby increasing the production of the neuroprotective soluble ectodomain (sAPPα). Our bioengineering strategy has the potential to be exploited as a next-generation gene therapy for AD.
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Mierke CT. The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling. Front Cell Dev Biol 2023; 11:1130823. [PMID: 36910158 PMCID: PMC9995898 DOI: 10.3389/fcell.2023.1130823] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/15/2023] [Indexed: 02/25/2023] Open
Abstract
The posttranslational proteolytic cleavage is a unique and irreversible process that governs the function and half-life of numerous proteins. Thereby the role of the family of A disintegrin and metalloproteases (ADAMs) plays a leading part. A member of this family, ADAM8, has gained attention in regulating disorders, such as neurogenerative diseases, immune function and cancer, by attenuating the function of proteins nearby the extracellular membrane leaflet. This process of "ectodomain shedding" can alter the turnover rate of a number of transmembrane proteins that function in cell adhesion and receptor signal transduction. In the past, the major focus of research about ADAMs have been on neurogenerative diseases, such as Alzheimer, however, there seems to be evidence for a connection between ADAM8 and cancer. The role of ADAMs in the field of cancer research has gained recent attention, but it has been not yet been extensively addressed. Thus, this review article highlights the various roles of ADAM8 with particular emphasis on pathological conditions, such as cancer and malignant cancer progression. Here, the shedding function, direct and indirect matrix degradation, effects on cancer cell mobility and transmigration, and the interplay of ADAM8 with matrix-embedded neighboring cells are presented and discussed. Moreover, the most probable mechanical impact of ADAM8 on cancer cells and their matrix environment is addressed and debated. In summary, this review presents recent advances in substrates/ligands and functions of ADAM8 in its new role in cancer and its potential link to cell mechanical properties and discusses matrix mechanics modifying properties. A deeper comprehension of the regulatory mechanisms governing the expression, subcellular localization, and activity of ADAM8 is expected to reveal appropriate drug targets that will permit a more tailored and fine-tuned modification of its proteolytic activity in cancer development and metastasis.
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Affiliation(s)
- Claudia Tanja Mierke
- Faculty of Physics and Earth Science, Biological Physics Division, Peter Debye Institute of Soft Matter Physics, Leipzig University, Leipzig, Germany
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Sharma D, Singh NK. The Biochemistry and Physiology of A Disintegrin and Metalloproteinases (ADAMs and ADAM-TSs) in Human Pathologies. Rev Physiol Biochem Pharmacol 2023; 184:69-120. [PMID: 35061104 DOI: 10.1007/112_2021_67] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metalloproteinases are a group of proteinases that plays a substantial role in extracellular matrix remodeling and its molecular signaling. Among these metalloproteinases, ADAMs (a disintegrin and metalloproteinases) and ADAM-TSs (ADAMs with thrombospondin domains) have emerged as highly efficient contributors mediating proteolytic processing of various signaling molecules. ADAMs are transmembrane metalloenzymes that facilitate the extracellular domain shedding of membrane-anchored proteins, cytokines, growth factors, ligands, and their receptors and therefore modulate their biological functions. ADAM-TSs are secretory, and soluble extracellular proteinases that mediate the cleavage of non-fibrillar extracellular matrix proteins. ADAMs and ADAM-TSs possess pro-domain, metalloproteinase, disintegrin, and cysteine-rich domains in common, but ADAM-TSs have characteristic thrombospondin motifs instead of the transmembrane domain. Most ADAMs and ADAM-TSs are activated by cleavage of pro-domain via pro-protein convertases at their N-terminus, hence directing them to various signaling pathways. In this article, we are discussing not only the structure and regulation of ADAMs and ADAM-TSs, but also the importance of these metalloproteinases in various human pathophysiological conditions like cardiovascular diseases, colorectal cancer, autoinflammatory diseases (sepsis/rheumatoid arthritis), Alzheimer's disease, proliferative retinopathies, and infectious diseases. Therefore, based on the emerging role of ADAMs and ADAM-TSs in various human pathologies, as summarized in this review, these metalloproteases can be considered as critical therapeutic targets and diagnostic biomarkers.
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Affiliation(s)
- Deepti Sharma
- Department of Ophthalmology, Visual and Anatomical Sciences, Integrative Biosciences Center (IBio), Wayne State University School of Medicine, Detroit, MI, USA
| | - Nikhlesh K Singh
- Department of Ophthalmology, Visual and Anatomical Sciences, Integrative Biosciences Center (IBio), Wayne State University School of Medicine, Detroit, MI, USA.
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8
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Minichino D, Lv K, Chu N, Tong W, Behrens EM. BRAF-V600E utilizes posttranscriptional mechanisms to amplify LPS-induced TNFα production in dendritic cells in a mouse model of Langerhans cell histiocytosis. J Leukoc Biol 2022; 112:1089-1104. [PMID: 35648675 PMCID: PMC9939017 DOI: 10.1002/jlb.3a0122-075rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Langerhans cell histiocytosis (LCH) is an inflammatory disease characterized by abnormal dendritic cells (DCs) with hyperactive ERK signaling, called "LCH cells." Since DCs rely on ERK signaling to produce inflammatory molecules in response to pathogenic cues, we hypothesized that hyperactive ERK enhances DCs inflammatory responses. We specifically investigated TLR4-induced TNFα production in LCH cells by utilizing the BRAF-V600Efl/+ :CD11c-Cre mouse model of LCH, which hyperactivates ERK in DCs. We measured LPS-induced TNFα production both in vivo and in vitro using splenic CD11c+ cells and bone marrow-derived DCs with or without pharmacologic BRAFV600E inhibition. We observed a reversible increase in secreted TNFα and a partially reversible increase in TNFα protein per cell, despite a decrease in TLR4 signaling and Tnfa transcripts compared with controls. We examined ERK-driven, posttranscriptional mechanisms that contribute to TNFα production and secretion using biochemical and cellular assays. We identified a reversible increase in TACE activation, the enzyme required for TNFα secretion, and most strikingly, an increase in protein translation, including TNFα. Defining the translatome through polysome-bound RNA sequencing revealed up-regulated translation of the LPS-response program. These data suggest hyperactive ERK signaling utilizes multiple posttranscriptional mechanisms to amplify inflammatory responses in DCs, advancing our understanding of LCH and basic DC biology.
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Affiliation(s)
- Danielle Minichino
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Pediatric Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kaosheng Lv
- Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Niansheng Chu
- Division of Pediatric Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Wei Tong
- Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Edward M Behrens
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Pediatric Rheumatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer. Cell Death Dis 2022; 13:888. [PMID: 36270986 PMCID: PMC9587286 DOI: 10.1038/s41419-022-05335-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 10/04/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
Histone deacetylase 6 (HDAC6), a member of the HDAC family, has been identified as a potential therapeutic target for tumor therapy, but the function and underlying mechanisms of HDAC6 in colon cancer are incompletely characterized. Our study showed that the infiltration ratio of M2 macrophages was increased in colon cancer tissues with high HDAC6 expression. Similarly, the knockdown of HDAC6 in colon cancer cells inhibited cocultured macrophage M2 polarization in vitro. Analysis of the antibody chip revealed that HDAC6 promoted sIL-6R release to enhance macrophage M2 polarization. Mass spectrometry and immunoprecipitation demonstrated that, mechanistically, HDAC6 interacted with transforming growth factor β-activated kinase 1 (TAK1), deacetylated TAK1 at T178 and promoted TAK1 phosphorylation. TAK1-p38 MAPK signaling could further increase the phosphorylation and activity of ADAM17, which is responsible for shedding of IL-6R. Notably, the expression of phosphorylated TAK1 was positively correlated with HDAC6 expression and macrophage M2 polarization in human colon cancer tissues. Our study revealed a new HDAC6-TAK1-ADAM17 regulatory axis that mediates sIL-6R release and macrophage polarization in colon cancer.
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The aminopeptidase B (Ap-B) is phosphorylated in HEK293 cells. Biochimie 2022; 201:204-212. [PMID: 35952945 DOI: 10.1016/j.biochi.2022.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 11/22/2022]
Abstract
Proteolysis is a post-translational modification (PTM) that affects the whole proteome. First regarded as only destructive, it is more precise than expected. It is finely regulated by other PTMs like phosphorylation. Aminopeptidase B (Ap-B), a M1 metallopeptidase, hydrolyses the peptide bond on the carbonyl side of basic residues at the NH2-terminus of peptides. 2D electrophoresis (2DE) was used to show that Ap-B is modified by phosphorylation. Detection of Ap-B by western blot after 2DE reveals several isoforms with different isoelectric points. Using alkaline phosphatase, Pro-Q Diamond phosphorylation-specific dye and kinase-specific inhibitors, we confirmed that Ap-B is phosphorylated. Phosphorylation can alter the structure of proteins leading to changes in their activity, localization, stability and association with other interacting molecules. We showed that Ap-B phosphorylation might delay its turnover. Our study illustrates the central role of the crosstalk between kinases and proteases in the regulation of many biological processes.
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Lysophosphatidylserine Induces MUC5AC Production via the Feedforward Regulation of the TACE-EGFR-ERK Pathway in Airway Epithelial Cells in a Receptor-Independent Manner. Int J Mol Sci 2022; 23:ijms23073866. [PMID: 35409225 PMCID: PMC8999057 DOI: 10.3390/ijms23073866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/20/2022] [Accepted: 03/29/2022] [Indexed: 02/05/2023] Open
Abstract
Lysophosphatidylserine (LysoPS) is an amphipathic lysophospholipid that mediates a broad spectrum of inflammatory responses through a poorly characterized mechanism. Because LysoPS levels can rise in a variety of pathological conditions, we sought to investigate LysoPS's potential role in airway epithelial cells that actively participate in lung homeostasis. Here, we report a previously unappreciated function of LysoPS in production of a mucin component, MUC5AC, in the airway epithelial cells. LysoPS stimulated lung epithelial cells to produce MUC5AC via signaling pathways involving TACE, EGFR, and ERK. Specifically, LysoPS- dependent biphasic activation of ERK resulted in TGF-α secretion and strong EGFR phosphorylation leading to MUC5AC production. Collectively, LysoPS induces the expression of MUC5AC via a feedback loop composed of proligand synthesis and its proteolysis by TACE and following autocrine EGFR activation. To our surprise, we were not able to find a role of GPCRs and TLR2, known LyoPS receptors in LysoPS-induced MUC5AC production in airway epithelial cells, suggesting a potential receptor-independent action of LysoPS during inflammation. This study provides new insight into the potential function and mechanism of LysoPS as an emerging lipid mediator in airway inflammation.
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ADAM17 Is an Essential Factor for the Infection of Bovine Cells with Pestiviruses. Viruses 2022; 14:v14020381. [PMID: 35215974 PMCID: PMC8875743 DOI: 10.3390/v14020381] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 01/19/2023] Open
Abstract
The entry of BVDV into bovine cells was studied using CRIB cells (cells resistant to infection with bovine viral diarrhea virus [BVDV]) that have evolved from MDBK cells by a spontaneous loss of susceptibility to BVDV. Recently, larger genetic deletions were reported but no correlation of the affected genes and the resistance to BVDV infection could be established. The metalloprotease ADAM17 was reported as an essential attachment factor for the related classical swine fever virus (CSFV). To assess whether ADAM17 might be involved in the resistance of CRIB-1 cells to pestiviruses, we analyzed its expression in CRIB-1 and MDBK cells. While ADAM17 protein was detectable in MBDK cells, it was absent from CRIB-1 cells. No functional full-length ADAM17 mRNA could be detected in CRIB cells and genetic analysis revealed the presence of two defective alleles. Transcomplementation of functional ADAM17 derived from MDBK cells in CRIB-1 cells resulted in a nearly complete reversion of their resistance to pestiviral infection. Our results demonstrate that ADAM17 is a key cellular factor for the pestivirus resistance of CRIB-1 cells and establishes its essential role for a broader range of pestiviruses.
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Eggert S, Kins S, Endres K, Brigadski T. Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer's disease. Biol Chem 2022; 403:43-71. [PMID: 34619027 DOI: 10.1515/hsz-2021-0330] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebrospinal fluid (CSF), and blood samples of Alzheimer's disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer's disease, and its cleavage fragments sAPPα and Aβ are known for their respective roles in neuroprotection and neuronal death. Common features of APP- and BDNF-signaling indicate a causal relationship in their mode of action. However, the interconnections of APP- and BDNF-signaling are not well understood. Therefore, we here discuss dimerization properties, localization, processing by α- and γ-secretase, relevance of the common interaction partners TrkB, p75, sorLA, and sortilin as well as shared signaling pathways of BDNF and sAPPα.
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Affiliation(s)
- Simone Eggert
- Department of Human Biology and Human Genetics, University of Kaiserslautern, Erwin-Schrödinger-Str. 13, D-67663 Kaiserslautern, Germany
| | - Stefan Kins
- Department of Human Biology and Human Genetics, University of Kaiserslautern, Erwin-Schrödinger-Str. 13, D-67663 Kaiserslautern, Germany
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg-University Mainz, D-55131 Mainz, Germany
| | - Tanja Brigadski
- Department of Informatics and Microsystem Technology, University of Applied Sciences Kaiserslautern, D-66482 Zweibrücken, Germany
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14
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Adu-Amankwaah J, Adzika GK, Adekunle AO, Ndzie Noah ML, Mprah R, Bushi A, Akhter N, Huang F, Xu Y, Adzraku SY, Nadeem I, Sun H. ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress. Front Cell Dev Biol 2021; 9:732952. [PMID: 34966735 PMCID: PMC8710811 DOI: 10.3389/fcell.2021.732952] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022] Open
Abstract
Heart failure development is characterized by persistent inflammation and progressive fibrosis owing to chronic catecholamine stress. In a chronic stress state, elevated catecholamines result in the overstimulation of beta-adrenergic receptors (βARs), specifically β2-AR coupling with Gαi protein. Gαi signaling increases the activation of receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs). Phosphorylation by these kinases is a common way to positively regulate the catalytic activity of A Disintegrin and Metalloprotease 17 (ADAM17), a metalloprotease that has grown much attention in recent years and has emerged as a chief regulatory hub in inflammation, fibrosis, and immunity due to its vital proteolytic activity. ADAM17 cleaves and activates proinflammatory cytokines and fibrotic factors that enhance cardiac dysfunction via inflammation and fibrosis. However, there is limited information on the cardiovascular aspect of ADAM17, especially in heart failure. Hence, this concise review provides a comprehensive insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. This review highlights the inflammatory and fibrotic roles of ADAM17’s substrates; Tumor Necrosis Factor α (TNFα), soluble interleukin-6 receptor (sIL-6R), and amphiregulin (AREG). Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed.
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Affiliation(s)
| | | | | | | | - Richard Mprah
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | | | - Nazma Akhter
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Fei Huang
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Yaxin Xu
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Seyram Yao Adzraku
- Key Laboratory of Bone Marrow Stem Cell, Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Iqra Nadeem
- Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Hong Sun
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
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15
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ADAM17 orchestrates Interleukin-6, TNFα and EGF-R signaling in inflammation and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119141. [PMID: 34610348 DOI: 10.1016/j.bbamcr.2021.119141] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023]
Abstract
It was realized in the 1990s that some membrane proteins such as TNFα, both TNF receptors, ligands of the EGF-R and the Interleukin-6 receptor are proteolytically cleaved and are shed from the cell membrane as soluble proteins. The major responsible protease is a metalloprotease named ADAM17. So far, close to 100 substrates, including cytokines, cytokine receptors, chemokines and adhesion molecules of ADAM17 are known. Therefore, ADAM17 orchestrates many different signaling pathways and is a central signaling hub in inflammation and carcinogenesis. ADAM17 plays an important role in the biology of Interleukin-6 (IL-6) since the generation of the soluble Interleukin-6 receptor (sIL-6R) is needed for trans-signaling, which has been identified as the pro-inflammatory activity of this cytokine. In contrast, Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is mostly regenerative and protective. Probably due to its broad substrate spectrum, ADAM17 is essential for life and most of the few human individuals identified with ADAM17 gene defects died at young age. Although the potential of ADAM17 as a therapeutic target has been recognized, specific blockade of ADAM17 is not trivial since the metalloprotease domain of ADAM17 shares high structural homology with other proteases, in particular matrix metalloproteases. Here, the critical functions of ADAM17 in IL-6, TNFα and EGF-R pathways and strategies of therapeutic interventions are discussed.
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16
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Johansen KH, Golec DP, Thomsen JH, Schwartzberg PL, Okkenhaug K. PI3K in T Cell Adhesion and Trafficking. Front Immunol 2021; 12:708908. [PMID: 34421914 PMCID: PMC8377255 DOI: 10.3389/fimmu.2021.708908] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function.
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Affiliation(s)
- Kristoffer H Johansen
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom.,Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, United States
| | - Dominic P Golec
- Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, United States
| | - Julie H Thomsen
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | | | - Klaus Okkenhaug
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
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17
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García-Alonso S, Romero-Pérez I, Gandullo-Sánchez L, Chinchilla L, Ocaña A, Montero JC, Pandiella A. Altered proTGFα/cleaved TGFα ratios offer new therapeutic strategies in renal carcinoma. J Exp Clin Cancer Res 2021; 40:256. [PMID: 34399807 PMCID: PMC8365933 DOI: 10.1186/s13046-021-02051-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/26/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Treatment of renal cancer has significantly improved with the arrival to the clinic of kinase inhibitors and immunotherapies. However, the disease is still incurable in advanced stages. The fact that several approved inhibitors for kidney cancer target receptor tyrosine kinases (RTKs) suggests that these proteins play a critical role in the pathophysiology of the disease. Based on these precedents, we decided to explore whether RTKs other than those targeted by approved drugs, contribute to the development of kidney cancer. METHODS The activation status of 49 RTKs in 44 paired samples of normal and tumor kidney tissue was explored using antibody arrays, with validation by western blotting. Genetic and pharmacologic approaches were followed to study the biological implications of targeting the epidermal growth factor receptor (EGFR) and its ligand Transforming Growth Factor-α (TGFα). RESULTS Activation of the EGFR was found in a substantial number of tumors. Moreover, kidney tumors expressed elevated levels of TGFα. Down-regulation of EGFR or TGFα using RNAi or their pharmacological targeting with blocking antibodies resulted in inhibition of the proliferation of in vitro cellular models of renal cancer. Importantly, differences in the molecular forms of TGFα expressed by tumors and normal tissues were found. In fact, tumor TGFα was membrane anchored, while that expressed by normal kidney tissue was proteolytically processed. CONCLUSIONS The EGFR-TGFα axis plays a relevant role in the pathophysiology of kidney cancer. This study unveils a distinctive feature in renal cell carcinomas, which is the presence of membrane-anchored TGFα. That characteristic could be exploited therapeutically to act on tumors expressing transmembrane TGFα, for example, with antibody drug conjugates that could recognize the extracellular region of that protein.
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Affiliation(s)
- Sara García-Alonso
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and CIBERONC. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Inés Romero-Pérez
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and CIBERONC. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Lucía Gandullo-Sánchez
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and CIBERONC. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Luis Chinchilla
- Pathology Service, University Hospital and IBSAL, Salamanca, Spain
| | | | - Juan Carlos Montero
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and CIBERONC. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
| | - Atanasio Pandiella
- Instituto de Biología Molecular y Celular del Cáncer, CSIC and CIBERONC. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
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18
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Hamdan D, Robinson LA. Role of the CX 3CL1-CX 3CR1 axis in renal disease. Am J Physiol Renal Physiol 2021; 321:F121-F134. [PMID: 34121453 DOI: 10.1152/ajprenal.00059.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines comprises key drivers of this process. Fractalkine [chemokine (C-X3-C motif) ligand 1 (CX3CL1)] is one of two unique chemokines synthesized as a transmembrane protein that undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, chemokine (C-X3-C motif) receptor 1 (CX3CR1), CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.
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Affiliation(s)
- Diana Hamdan
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Lisa A Robinson
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
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19
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Yang G, Cui M, Jiang W, Sheng J, Yang Y, Zhang X. Molecular switch in human diseases-disintegrin and metalloproteinases, ADAM17. Aging (Albany NY) 2021; 13:16859-16872. [PMID: 34182543 PMCID: PMC8266367 DOI: 10.18632/aging.203200] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 05/18/2021] [Indexed: 01/01/2023]
Abstract
The ADAMs (a disintegrin and metalloproteinase) are a family of cell surface proteins with crucial roles in the regulation of cell adhesion, cell proliferation to migration, proteolysis and cell signaling transduction pathways. Among these enzymes, the ADAM17 shows significant effects in the “ectodomain shedding” of its substrates such as cytokines (e.g., tumor necrosis factor α, TNFα), growth factors (e.g., epidermal growth factor, EGF), adhesion proteins (e.g., L-selectin), and their receptors (e.g., IL-6R and TNFα). Several studies focus on the underlying molecular mechanisms of ADAM17 in diseased conditions. Here, we took several different approaches to elucidate the function of ADAM17, the participation of ADAM17 in several human diseases, and the potential as targeted therapy reagents. As more and more studies verify the miRNA-mediated expression variation of ADAM17, the specific regulation network of miRNAs and ADAM17 was exploited in this review as well.
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Affiliation(s)
- Guang Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Yongsheng Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, P.R. China
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20
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Lora J, Weskamp G, Li TM, Maretzky T, Shola DTN, Monette S, Lichtenthaler SF, Lu TT, Yang C, Blobel CP. Targeted truncation of the ADAM17 cytoplasmic domain in mice results in protein destabilization and a hypomorphic phenotype. J Biol Chem 2021; 296:100733. [PMID: 33957124 PMCID: PMC8191336 DOI: 10.1016/j.jbc.2021.100733] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/21/2021] [Accepted: 04/28/2021] [Indexed: 12/28/2022] Open
Abstract
A disintegrin and metalloprotease 17 (ADAM17) is a cell-surface metalloprotease that serves as the principle sheddase for tumor necrosis factor α (TNFα), interleukin-6 receptor (IL-6R), and several ligands of the epidermal growth factor receptor (EGFR), regulating these crucial signaling pathways. ADAM17 activation requires its transmembrane domain, but not its cytoplasmic domain, and little is known about the role of this domain in vivo. To investigate, we used CRISPR-Cas9 to mutate the endogenous Adam17 locus in mice to produce a mutant ADAM17 lacking its cytoplasmic domain (Adam17Δcyto). Homozygous Adam17Δcyto animals were born at a Mendelian ratio and survived into adulthood with slightly wavy hair and curled whiskers, consistent with defects in ADAM17/EGFR signaling. At birth, Adam17Δcyto mice resembled Adam17−/− mice in that they had open eyes and enlarged semilunar heart valves, but they did not have bone growth plate defects. The deletion of the cytoplasmic domain resulted in strongly decreased ADAM17 protein levels in all tissues and cells examined, providing a likely cause for the hypomorphic phenotype. In functional assays, Adam17Δcyto mouse embryonic fibroblasts and bone-marrow-derived macrophages had strongly reduced ADAM17 activity, consistent with the reduced protein levels. Nevertheless, ADAM17Δcyto could be stimulated by PMA, a well-characterized posttranslational activator of ADAM17, corroborating that the cytoplasmic domain of endogenous ADAM17 is not required for its rapid response to PMA. Taken together, these results provide the first evidence that the cytoplasmic domain of ADAM17 plays a pivotal role in vivo in regulating ADAM17 levels and function.
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Affiliation(s)
- Jose Lora
- Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, New York, USA; Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA
| | - Gisela Weskamp
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA
| | - Thomas M Li
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA
| | - Thorsten Maretzky
- Inflammation Program and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Dorjee T N Shola
- CRISPR and Genome Editing Resource Center, Rockefeller University, New York, New York, USA
| | - Sébastien Monette
- Tri-Institutional Laboratory of Comparative Pathology, Sloan-Kettering Institute, New York, New York, USA
| | - Stefan F Lichtenthaler
- German Center for Neurodegenerative Diseases (DZNE), Technical University of Munich, Munich, Germany; Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Technical University of Munich, Munich, Germany; Institute for Advanced Study, Technical University of Munich, Garching, Germany
| | - Theresa T Lu
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
| | - Chingwen Yang
- CRISPR and Genome Editing Resource Center, Rockefeller University, New York, New York, USA
| | - Carl P Blobel
- Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, New York, USA; Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA; Institute for Advanced Study, Technical University of Munich, Garching, Germany; Department of Medicine, Weill Cornell Medicine, New York, New York, USA; Department of Biophysics, Physiology and Systems Biology, Weill Cornell Medicine, New York, New York, USA.
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21
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Kawai T, Elliott KJ, Scalia R, Eguchi S. Contribution of ADAM17 and related ADAMs in cardiovascular diseases. Cell Mol Life Sci 2021; 78:4161-4187. [PMID: 33575814 PMCID: PMC9301870 DOI: 10.1007/s00018-021-03779-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/23/2020] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Abstract
A disintegrin and metalloproteases (ADAMs) are key mediators of cell signaling by ectodomain shedding of various growth factors, cytokines, receptors and adhesion molecules at the cellular membrane. ADAMs regulate cell proliferation, cell growth, inflammation, and other regular cellular processes. ADAM17, the most extensively studied ADAM family member, is also known as tumor necrosis factor (TNF)-α converting enzyme (TACE). ADAMs-mediated shedding of cytokines such as TNF-α orchestrates immune system or inflammatory cascades and ADAMs-mediated shedding of growth factors causes cell growth or proliferation by transactivation of the growth factor receptors including epidermal growth factor receptor. Therefore, increased ADAMs-mediated shedding can induce inflammation, tissue remodeling and dysfunction associated with various cardiovascular diseases such as hypertension and atherosclerosis, and ADAMs can be a potential therapeutic target in these diseases. In this review, we focus on the role of ADAMs in cardiovascular pathophysiology and cardiovascular diseases. The main aim of this review is to stimulate new interest in this area by highlighting remarkable evidence.
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Affiliation(s)
- Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Katherine J Elliott
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA.
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22
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Huang H. Proteolytic Cleavage of Receptor Tyrosine Kinases. Biomolecules 2021; 11:biom11050660. [PMID: 33947097 PMCID: PMC8145142 DOI: 10.3390/biom11050660] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/15/2021] [Accepted: 04/26/2021] [Indexed: 01/18/2023] Open
Abstract
The receptor tyrosine kinases (RTKs) are a large family of cell-surface receptors, which are essential components of signal transduction pathways. There are more than fifty human RTKs that can be grouped into multiple RTK subfamilies. RTKs mediate cellular signaling transduction, and they play important roles in the regulation of numerous cellular processes. The dysregulation of RTK signaling is related to various human diseases, including cancers. The proteolytic cleavage phenomenon has frequently been found among multiple receptor tyrosine kinases. More and more information about proteolytic cleavage in RTKs has been discovered, providing rich insight. In this review, we summarize research about different aspects of RTK cleavage, including its relation to cancer, to better elucidate this phenomenon. This review also presents proteolytic cleavage in various members of the RTKs.
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Affiliation(s)
- Hao Huang
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; or
- Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
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23
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Jundi B, Geraghty P. ADAM17: A Therapeutic Target for Patients with Emphysema? Am J Respir Cell Mol Biol 2021; 64:155-157. [PMID: 33522887 PMCID: PMC7874393 DOI: 10.1165/rcmb.2020-0467ed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Bakr Jundi
- Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York
| | - Patrick Geraghty
- Department of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York
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24
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Strategies to Target ADAM17 in Disease: From its Discovery to the iRhom Revolution. Molecules 2021; 26:molecules26040944. [PMID: 33579029 PMCID: PMC7916773 DOI: 10.3390/molecules26040944] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.
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25
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Saad MI, McLeod L, Hodges C, Vlahos R, Rose-John S, Ruwanpura S, Jenkins BJ. ADAM17 Deficiency Protects against Pulmonary Emphysema. Am J Respir Cell Mol Biol 2021; 64:183-195. [PMID: 33181031 DOI: 10.1165/rcmb.2020-0214oc] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 10/01/2020] [Indexed: 12/22/2022] Open
Abstract
Pulmonary emphysema is the major debilitating component of chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality worldwide. The ADAM17 (A disintegrin and metalloproteinase 17) protease mediates inflammation via ectodomain shedding of numerous proinflammatory cytokines, cytokine receptors, and adhesion molecules; however, its role in the pathogenesis of emphysema and COPD is poorly understood. This study aims to define the role of the protease ADAM17 in the pathogenesis of pulmonary emphysema. ADAM17 protein expression and activation was investigated in lung biopsies from patients with emphysema, as well as lungs of the emphysematous gp130F/F mouse model and an acute (4 d) cigarette smoke (CS)-induced lung pathology model. The Adam17ex/ex mice, which display significantly reduced global ADAM17 expression, were coupled with emphysema-prone gp130F/F mice to produce gp130F/F:Adam17ex/ex. Both Adam17ex/ex and wild-type mice were subjected to acute CS exposure. Histological, immunohistochemical, immunofluorescence, and molecular analyses as well as lung function tests were performed to assess pulmonary emphysema, inflammation, and alveolar cell apoptosis. ADAM17 was hyperphosphorylated in the lungs of patients with emphysema and also in emphysematous gp130F/F and CS-exposed mice. ADAM17 deficiency ameliorated the development of pulmonary emphysema in gp130F/F mice by suppressing elevated alveolar cell apoptosis. In addition, genetic blockade of ADAM17 protected mice from CS-induced pulmonary inflammation and alveolar cell apoptosis. Our study places the protease ADAM17 as a central molecular switch implicated in the development of pulmonary emphysema, which paves the way for using ADAM17 inhibitors as potential therapeutic agents to treat COPD and emphysema.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Louise McLeod
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Christopher Hodges
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Ross Vlahos
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia; and
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
| | - Saleela Ruwanpura
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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Functional Characterization of Colon-Cancer-Associated Variants in ADAM17 Affecting the Catalytic Domain. Biomedicines 2020; 8:biomedicines8110463. [PMID: 33143292 PMCID: PMC7692748 DOI: 10.3390/biomedicines8110463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/17/2020] [Accepted: 10/29/2020] [Indexed: 12/24/2022] Open
Abstract
Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called shedding. A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease.
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Saad MI, McLeod L, Yu L, Ebi H, Ruwanpura S, Sagi I, Rose-John S, Jenkins BJ. The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis. Carcinogenesis 2020; 41:527-538. [PMID: 31257400 DOI: 10.1093/carcin/bgz123] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/31/2019] [Accepted: 06/24/2019] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and receptors, and therefore is an attractive target in cancer. However, the role of ADAM17 in promoting tobacco smoke carcinogen-induced lung carcinogenesis is unknown. The hypomorphic Adam17ex/ex mice-characterized by reduced global ADAM17 expression-were backcrossed onto the NNK-sensitive pseudo-A/J background. CRISPR-driven and inhibitor-based (GW280264X, and ADAM17 prodomain) ADAM17 targeting was employed in the human lung adenocarcinoma cell lines A549 and NCI-H23. Human lung cancer biopsies were also used for analyses. The Adam17ex/ex mice displayed marked protection against NNK-induced lung adenocarcinoma. Specifically, the number and size of lung lesions in NNK-treated pseudo-A/J Adam17ex/ex mice were significantly reduced compared with wild-type littermate controls. This was associated with lower proliferative index throughout the lung epithelium. ADAM17 targeting in A549 and NCI-H23 cells led to reduced proliferative and colony-forming capacities. Notably, among select ADAM17 substrates, ADAM17 deficiency abrogated shedding of the soluble IL-6 receptor (sIL-6R), which coincided with the blockade of sIL-6R-mediated trans-signaling via ERK MAPK cascade. Furthermore, NNK upregulated phosphorylation of p38 MAPK, whose pharmacological inhibition suppressed ADAM17 threonine phosphorylation. Importantly, ADAM17 threonine phosphorylation was significantly upregulated in human lung adenocarcinoma with smoking history compared with their cancer-free controls. Our study identifies the ADAM17/sIL-6R/ERK MAPK axis as a candidate therapeutic strategy against tobacco smoke-associated lung carcinogenesis.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Louise McLeod
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Liang Yu
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Hiromichi Ebi
- Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.,Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Saleela Ruwanpura
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
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28
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Aikin TJ, Peterson AF, Pokrass MJ, Clark HR, Regot S. MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression. eLife 2020; 9:e60541. [PMID: 32940599 PMCID: PMC7498266 DOI: 10.7554/elife.60541] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/19/2020] [Indexed: 12/19/2022] Open
Abstract
A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained-but not pulsatile-ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.
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Affiliation(s)
- Timothy J Aikin
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of MedicineBaltimoreUnited States
- The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Amy F Peterson
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of MedicineBaltimoreUnited States
- The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Michael J Pokrass
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of MedicineBaltimoreUnited States
- The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Helen R Clark
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of MedicineBaltimoreUnited States
- The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Sergi Regot
- Department of Molecular Biology and Genetics, The Johns Hopkins University School of MedicineBaltimoreUnited States
- The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of MedicineBaltimoreUnited States
- Department of Oncology, The Johns Hopkins University School of MedicineBaltimoreUnited States
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Schumacher N, Rose-John S, Schmidt-Arras D. ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation. Int J Mol Sci 2020; 21:ijms21145133. [PMID: 32698506 PMCID: PMC7404302 DOI: 10.3390/ijms21145133] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also termed ectodomain shedding. Members of the family of A disintegrin and metalloproteases (ADAM) are major mediators of ectodomain shedding and therefore initiators of paracrine signal transduction. In this review, we summarize the current knowledge on how ADAM proteases on tumour cells but also on cells of the tumour micro-environment contribute to the formation of gastrointestinal tumours, and discuss how these processes can be exploited pharmacologically.
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Hino N, Rossetti L, Marín-Llauradó A, Aoki K, Trepat X, Matsuda M, Hirashima T. ERK-Mediated Mechanochemical Waves Direct Collective Cell Polarization. Dev Cell 2020; 53:646-660.e8. [PMID: 32497487 DOI: 10.1016/j.devcel.2020.05.011] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/25/2020] [Accepted: 05/11/2020] [Indexed: 01/02/2023]
Abstract
During collective migration of epithelial cells, the migration direction is aligned over a tissue-scale expanse. Although the collective cell migration is known to be directed by mechanical forces transmitted via cell-cell junctions, it remains elusive how the intercellular force transmission is coordinated with intracellular biochemical signaling to achieve collective movements. Here, we show that intercellular coupling of extracellular signal-regulated kinase (ERK)-mediated mechanochemical feedback yields long-distance transmission of guidance cues. Mechanical stretch activates ERK through epidermal growth factor receptor (EGFR) activation, and ERK activation triggers cell contraction. The contraction of the activated cell pulls neighboring cells, evoking another round of ERK activation and contraction in the neighbors. Furthermore, anisotropic contraction based on front-rear polarization guarantees unidirectional propagation of ERK activation, and in turn, the ERK activation waves direct multicellular alignment of the polarity, leading to long-range ordered migration. Our findings reveal that mechanical forces mediate intercellular signaling underlying sustained transmission of guidance cues for collective cell migration.
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Affiliation(s)
- Naoya Hino
- Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
| | - Leone Rossetti
- Institute for Bioengineering of Catalonia, Barcelona 08028, Spain
| | | | - Kazuhiro Aoki
- Quantitative Biology Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Division of Quantitative Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan; Department of Basic Biology, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan
| | - Xavier Trepat
- Institute for Bioengineering of Catalonia, Barcelona 08028, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain
| | - Michiyuki Matsuda
- Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
| | - Tsuyoshi Hirashima
- Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Japan Science and Technology Agency, PRESTO, Sakyo-ku, Kyoto 606-8501, Japan.
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Phosphorylation Signaling in APP Processing in Alzheimer's Disease. Int J Mol Sci 2019; 21:ijms21010209. [PMID: 31892243 PMCID: PMC6981488 DOI: 10.3390/ijms21010209] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/23/2019] [Accepted: 12/24/2019] [Indexed: 12/13/2022] Open
Abstract
The abnormal accumulation of amyloid-β (Aβ) in the central nervous system is a hallmark of Alzheimer’s disease (AD). The regulation of the processing of the single- transmembrane amyloid precursor protein (APP) plays an important role in the generation of Aβ in the brain. The phosphorylation of APP and key enzymes involved in the proteolytic processing of APP has been demonstrated to be critical for modulating the generation of Aβ by either altering the subcellular localization of APP or changing the enzymatic activities of the secretases responsible for APP processing. In addition, the phosphorylation may also have an impact on the physiological function of these proteins. In this review, we summarize the kinases and signaling pathways that may participate in regulating the phosphorylation of APP and secretases and how this further affects the function and processing of APP and Aβ pathology. We also discuss the potential of approaches that modulate these phosphorylation-signaling pathways or kinases as interventions for AD pathology.
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Regulation of Fibrotic Processes in the Liver by ADAM Proteases. Cells 2019; 8:cells8101226. [PMID: 31601007 PMCID: PMC6830092 DOI: 10.3390/cells8101226] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/02/2019] [Accepted: 10/04/2019] [Indexed: 12/18/2022] Open
Abstract
Fibrosis in the liver is mainly associated with the activation of hepatic stellate cells (HSCs). Both activation and clearance of HSCs can be mediated by ligand–receptor interactions. Members of the a disintegrin and metalloprotease (ADAM) family are involved in the proteolytic release of membrane-bound ligands and receptor ectodomains and the remodelling of the extracellular matrix. ADAM proteases are therefore major regulators of intercellular signalling pathways. In the present review we discuss how ADAM proteases modulate pro- and anti-fibrotic processes and how ADAM proteases might be harnessed therapeutically in the future.
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Pelullo M, Nardozza F, Zema S, Quaranta R, Nicoletti C, Besharat ZM, Felli MP, Cerbelli B, d'Amati G, Palermo R, Capalbo C, Talora C, Di Marcotullio L, Giannini G, Checquolo S, Screpanti I, Bellavia D. Kras/ADAM17-Dependent Jag1-ICD Reverse Signaling Sustains Colorectal Cancer Progression and Chemoresistance. Cancer Res 2019; 79:5575-5586. [PMID: 31506332 DOI: 10.1158/0008-5472.can-19-0145] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 05/17/2019] [Accepted: 09/06/2019] [Indexed: 11/16/2022]
Abstract
Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic Ras mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial-mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in colorectal cancer tumor biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism. SIGNIFICANCE: These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.
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Affiliation(s)
- Maria Pelullo
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | | | - Sabrina Zema
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Roberta Quaranta
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Carmine Nicoletti
- Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology, Sapienza University, Rome, Italy
| | | | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Bruna Cerbelli
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University, Rome, Italy
| | - Giulia d'Amati
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University, Rome, Italy
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Carlo Capalbo
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, Sapienza University, Laboratory affiliated to Istituto Pasteur Italia, Italy
| | - Giuseppe Giannini
- Department of Molecular Medicine, Sapienza University, Laboratory affiliated to Istituto Pasteur Italia, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy.
| | | | - Diana Bellavia
- Department of Molecular Medicine, Sapienza University, Rome, Italy.
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Camodeca C, Cuffaro D, Nuti E, Rossello A. ADAM Metalloproteinases as Potential Drug Targets. Curr Med Chem 2019; 26:2661-2689. [PMID: 29589526 DOI: 10.2174/0929867325666180326164104] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 03/12/2018] [Accepted: 03/12/2018] [Indexed: 01/01/2023]
Abstract
The ADAMs, together with ADAMTSs and snake venom metalloproteases (SVMPs), are members of the Adamalysin family. Differences in structural organization, functions and localization are known and their domains, catalytic or non-catalytic, show key roles in the substrate recognition and protease activity. Some ADAMs, as membrane-bound enzymes, show sheddase activity. Sheddases are key to modulation of functional proteins such as the tumor necrosis factor, growth factors, cytokines and their receptors, adhesion proteins, signaling molecules and stress molecules involved in immunity. These activities take part in the regulation of several physiological and pathological processes including inflammation, tumor growth, metastatic progression and infectious diseases. On these bases, some ADAMs are currently investigated as drug targets to develop new alternative therapies in many fields of medicine. This review will be focused on these aspects.
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Affiliation(s)
- Caterina Camodeca
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
| | - Doretta Cuffaro
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
| | - Elisa Nuti
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
| | - Armando Rossello
- Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, Italy
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Saad MI, Rose-John S, Jenkins BJ. ADAM17: An Emerging Therapeutic Target for Lung Cancer. Cancers (Basel) 2019; 11:E1218. [PMID: 31438559 PMCID: PMC6769596 DOI: 10.3390/cancers11091218] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/07/2019] [Accepted: 08/17/2019] [Indexed: 12/23/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). KRAS mutations are a major driver of LAC, and are closely related to cigarette smoking, unlike mutations in the epidermal growth factor receptor (EGFR) which arise in never-smokers. Although the past two decades have seen fundamental progress in the treatment and diagnosis of NSCLC, NSCLC still is predominantly diagnosed at an advanced stage when therapeutic interventions are mostly palliative. A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-α (TNFα)-converting enzyme (TACE), is responsible for the protease-driven shedding of more than 70 membrane-tethered cytokines, growth factors and cell surface receptors. Among these, the soluble interleukin-6 receptor (sIL-6R), which drives pro-inflammatory and pro-tumourigenic IL-6 trans-signaling, along with several EGFR family ligands, are the best characterised. This large repertoire of substrates processed by ADAM17 places it as a pivotal orchestrator of a myriad of physiological and pathological processes associated with the initiation and/or progression of cancer, such as cell proliferation, survival, regeneration, differentiation and inflammation. In this review, we discuss recent research implicating ADAM17 as a key player in the development of LAC, and highlight the potential of ADAM17 inhibition as a promising therapeutic strategy to tackle this deadly malignancy.
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Affiliation(s)
- Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University, D-24098 Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia.
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Kopp R, Krautloher A, Ramírez-Fernández A, Nicke A. P2X7 Interactions and Signaling - Making Head or Tail of It. Front Mol Neurosci 2019; 12:183. [PMID: 31440138 PMCID: PMC6693442 DOI: 10.3389/fnmol.2019.00183] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 07/11/2019] [Indexed: 12/14/2022] Open
Abstract
Extracellular adenine nucleotides play important roles in cell-cell communication and tissue homeostasis. High concentrations of extracellular ATP released by dying cells are sensed as a danger signal by the P2X7 receptor, a non-specific cation channel. Studies in P2X7 knockout mice and numerous disease models have demonstrated an important role of this receptor in inflammatory processes. P2X7 activation has been shown to induce a variety of cellular responses that are not usually associated with ion channel function, for example changes in the plasma membrane composition and morphology, ectodomain shedding, activation of lipases, kinases, and transcription factors, as well as cytokine release and apoptosis. In contrast to all other P2X family members, the P2X7 receptor contains a long intracellular C-terminus that constitutes 40% of the whole protein and is considered essential for most of these effects. So far, over 50 different proteins have been identified to physically interact with the P2X7 receptor. However, few of these interactions have been confirmed in independent studies and for the majority of these proteins, the interaction domains and the physiological consequences of the interactions are only poorly described. Also, while the structure of the P2X7 extracellular domain has recently been resolved, information about the organization and structure of its C-terminal tail remains elusive. After shortly describing the structure and assembly of the P2X7 receptor, this review gives an update of the identified or proposed interaction domains within the P2X7 C-terminus, describes signaling pathways in which this receptor has been involved, and provides an overlook of the identified interaction partners.
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Affiliation(s)
- Robin Kopp
- Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Anna Krautloher
- Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Antonio Ramírez-Fernández
- Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Annette Nicke
- Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Munich, Germany
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Palau V, Pascual J, Soler MJ, Riera M. Role of ADAM17 in kidney disease. Am J Physiol Renal Physiol 2019; 317:F333-F342. [DOI: 10.1152/ajprenal.00625.2018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
It is known that the renin-angiotensin system plays a major role in the pathophysiology of cardiovascular disease and renal injury. Within the renin-angiotensin system, angiotensin-converting enzyme 2 (ACE2) cleaves ANG II to generate ANG(1–7) peptide, which counteracts the adverse effects of ANG II accumulation. ACE2 can undergo cleavage or shedding to release the catalytically active ectodomain into the circulation by a disintegrin and metalloprotease (ADAM)17, also known as TNF-α-converting enzyme. ADAM17 is involved in many pathological processes such as cancer, inflammatory diseases, neurological diseases, cardiovascular diseases, atherosclerosis, diabetes, and hypertension. Clinical and experimental studies have shown that ADAM17 is involved in chronic kidney disease (CKD) with a proinflammatory and profibrotic role, suggesting that it could be an important mediator of CKD progression. ADAM17 inhibition attenuates fibrosis and inflammation, suggesting that its inhibition may be a possible new valuable therapeutic tool in fibrotic kidney disease treatment. In addition, in renal disease, some experimental studies have demonstrated that ADAM17 is differently expressed in the kidney. Thus, ADAM17 is highly expressed in distal renal tubules and increased in the whole kidney in diabetic models. In this article, we will review the role of ADAM17 under physiological and pathological conditions. We will mainly focus on the importance of ADAM17 in the context of CKD.
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Affiliation(s)
- Vanesa Palau
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Maria José Soler
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Marta Riera
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
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Status update on iRhom and ADAM17: It's still complicated. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1567-1583. [PMID: 31330158 DOI: 10.1016/j.bbamcr.2019.06.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/26/2019] [Accepted: 06/28/2019] [Indexed: 02/06/2023]
Abstract
Several membrane-bound proteins with a single transmembrane domain are subjected to limited proteolysis at the cell surface. This cleavage leads to the release of their biologically active ectodomains, which can trigger different signalling pathways. In many cases, this ectodomain shedding is mediated by members of the family of a disintegrins and metalloproteinases (ADAMs). ADAM17 in particular is responsible for the cleavage of several proinflammatory mediators, growth factors, receptors and adhesion molecules. Due to its direct involvement in the release of these signalling molecules, ADAM17 can be positively and negatively involved in various physiological processes as well as in inflammatory, fibrotic and malignant pathologies. This central role of ADAM17 in a variety of processes requires strict multi-level regulation, including phosphorylation, various conformational changes and endogenous inhibitors. Recent research has shown that an early, crucial control mechanism is interaction with certain adapter proteins identified as iRhom1 and iRhom2, which are pseudoproteases of the rhomboid superfamily. Thus, iRhoms have also a decisive influence on physiological and pathophysiological signalling processes regulated by ADAM17. Their characteristic gene expression profiles, the specific consequences of gene knockouts and finally the occurrence of disease-associated mutations suggest that iRhom1 and iRhom2 undergo different gene regulation in order to fulfil their function in different cell types and are therefore only partially redundant. Therefore, there is not only interest in ADAM17, but also in iRhoms as therapeutic targets. However, to exploit the therapeutic potential, the regulation of ADAM17 activity and in particular its interaction with iRhoms must be well understood.
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Schubert K, Collins LE, Green P, Nagase H, Troeberg L. LRP1 Controls TNF Release via the TIMP-3/ADAM17 Axis in Endotoxin-Activated Macrophages. THE JOURNAL OF IMMUNOLOGY 2019; 202:1501-1509. [PMID: 30659107 DOI: 10.4049/jimmunol.1800834] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 12/16/2018] [Indexed: 11/19/2022]
Abstract
The metalloproteinase ADAM17 plays a pivotal role in initiating inflammation by releasing TNF from its precursor. Prolonged TNF release causes many chronic inflammatory diseases, indicating that tight regulation of ADAM17 activity is essential for resolution of inflammation. In this study, we report that the endogenous ADAM17 inhibitor TIMP-3 inhibits ADAM17 activity only when it is bound to the cell surface and that cell surface levels of TIMP-3 in endotoxin-activated human macrophages are dynamically controlled by the endocytic receptor LRP1. Pharmacological blockade of LRP1 inhibited endocytic clearance of TIMP-3, leading to an increase in cell surface levels of the inhibitor that blocked TNF release. Following LPS stimulation, TIMP-3 levels on the surface of macrophages increased 4-fold within 4 h and continued to accumulate at 6 h, before a return to baseline levels at 8 h. This dynamic regulation of cell surface TIMP-3 levels was independent of changes in TIMP-3 mRNA levels, but correlated with shedding of LRP1. These results shed light on the basic mechanisms that maintain a regulated inflammatory response and ensure its timely resolution.
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Affiliation(s)
- Kristin Schubert
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Laura E Collins
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Patricia Green
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Hideaki Nagase
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom
| | - Linda Troeberg
- Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom
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Xing Z, Wei L, Jiang X, Conroy J, Glenn S, Bshara W, Yu T, Pao A, Tanaka S, Kawai A, Choi C, Wang J, Liu S, Morrison C, Yu YE. Analysis of mutations in primary and metastatic synovial sarcoma. Oncotarget 2018; 9:36878-36888. [PMID: 30627328 PMCID: PMC6305143 DOI: 10.18632/oncotarget.26416] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Synovial sarcoma is the most common pediatric non-rhabdomyosarcoma soft tissue sarcoma and accounts for about 8-10% of all soft tissue sarcoma in childhood and adolescence. The presence of a chromosomal translocation-associated SS18-SSX-fusion gene is causally linked to development of primary synovial sarcoma. Metastases occur in approximately 50-70% of synovial sarcoma cases with yet unknown mechanisms, which led to about 70-80% mortality rate in five years. To explore the possibilities to investigate metastatic mechanisms of synovial sarcoma, we carried out the first genome-wide search for potential genetic biomarkers and drivers associated with metastasis by comparative mutational profiling of 18 synovial sarcoma samples isolated from four patients carrying the primary tumors and another four patients carrying the metastatic tumors through whole exome sequencing. Selected from the candidates yielded from this effort, we examined the effect of the multiple missense mutations of ADAM17, which were identified solely in metastatic synovial sarcoma. The mutant alleles as well as the wild-type control were expressed in the mammalian cells harboring the SS18-SSX1 fusion gene. The ADAM17-P729H mutation was shown to enhance cell migration, a phenotype associated with metastasis. Therefore, like ADAM17-P729H, other mutations we identified solely in metastatic synovial sarcoma may also have the potential to serve as an entry point for unraveling the metastatic mechanisms of synovial sarcoma.
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Affiliation(s)
- Zhuo Xing
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Lei Wei
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Xiaoling Jiang
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jeffrey Conroy
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,OmniSeq Inc., Buffalo, NY, USA
| | - Sean Glenn
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,OmniSeq Inc., Buffalo, NY, USA
| | - Wiam Bshara
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Tao Yu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Annie Pao
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Shinya Tanaka
- Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Christopher Choi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jianmin Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Carl Morrison
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,OmniSeq Inc., Buffalo, NY, USA.,Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Y Eugene Yu
- The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA.,Genetics, Genomics and Bioinformatics Program, State University of New York at Buffalo, Buffalo, NY, USA
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Cabron AS, El Azzouzi K, Boss M, Arnold P, Schwarz J, Rosas M, Dobert JP, Pavlenko E, Schumacher N, Renné T, Taylor PR, Linder S, Rose-John S, Zunke F. Structural and Functional Analyses of the Shedding Protease ADAM17 in HoxB8-Immortalized Macrophages and Dendritic-like Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:3106-3118. [PMID: 30355783 PMCID: PMC6215251 DOI: 10.4049/jimmunol.1701556] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 09/16/2018] [Indexed: 01/19/2023]
Abstract
A disintegrin and metalloproteinase (ADAM) 17 has been implicated in many shedding processes. Major substrates of ADAM17 are TNF-α, IL-6R, and ligands of the epidermal growth factor receptor. The essential role of the protease is emphasized by the fact that ADAM17 deficiency is lethal in mice. To study ADAM17 function in vivo, we generated viable hypomorphic ADAM17 mice called ADAM17ex/ex mice. Recent studies indicated regulation of proteolytic ADAM17 activity by cellular processes such as cytoplasmic phosphorylation and removal of the prodomain by furin cleavage. Maturation and thus activation of ADAM17 is not fully understood. So far, studies of ADAM17 maturation have been mainly limited to mouse embryonic fibroblasts or transfected cell lines relying on nonphysiologic stimuli such as phorbol esters, thus making interpretation of the results difficult in a physiologic context. In this article, we present a robust cell system to study ADAM17 maturation and function in primary cells of the immune system. To this end, HoxB8 conditionally immortalized macrophage precursor cell lines were derived from bone marrow of wild-type and hypomorphic ADAM17ex/ex mice, which are devoid of measurable ADAM17 activity. ADAM17 mutants were stably expressed in macrophage precursor cells, differentiated to macrophages under different growth factor conditions (M-CSF versus GM-CSF), and analyzed for cellular localization, proteolytic activity, and podosome disassembly. Our study reveals maturation and activity of ADAM17 in a more physiological-immune cell system. We show that this cell system can be further exploited for genetic modifications of ADAM17 and for studying its function in immune cells.
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Affiliation(s)
- Anne-Sophie Cabron
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Karim El Azzouzi
- Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246 Hamburg, Germany
| | - Melanie Boss
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Philipp Arnold
- Institute of Anatomy, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Jeanette Schwarz
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Marcela Rosas
- Division of Infection and Immunity, Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff CF10 3AT, United Kingdom
| | - Jan Philipp Dobert
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Egor Pavlenko
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Neele Schumacher
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
| | - Thomas Renné
- Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Solna, SE-171 76 Stockholm, Sweden; and
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Philip R Taylor
- Division of Infection and Immunity, Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff CF10 3AT, United Kingdom
| | - Stefan Linder
- Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, 20246 Hamburg, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany;
| | - Friederike Zunke
- Institute of Biochemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany;
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42
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iNOS promotes CD24 +CD133 + liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci U S A 2018; 115:E10127-E10136. [PMID: 30297396 PMCID: PMC6205478 DOI: 10.1073/pnas.1722100115] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
CD24+CD133+ liver cancer stem cells (LCSCs) express higher levels of the inducible nitric oxide synthase (iNOS) and possess self-renewal and tumor growth properties. iNOS is associated with more aggressive hepatocellular carcinoma (HCC), leading to the upregulation of Notch1 signaling. The activation of Notch1 by iNOS/NO is dependent on cGMP/PKG-mediated activation of TACE and upregulation of iRhom-2. The expression of iNOS, CD24, and CD133 correlates with the expression of activated TACE and Notch signaling in more aggressive human HCC. These findings have implications for understanding how LCSCs are regulated in the setting of chronic inflammation, where signals to upregulate iNOS are often present. Targeting iNOS could have therapeutic benefit in HCC. The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes. The expression of iNOS in CD24+CD133+ LCSCs, but not CD24−CD133− LCSCs, promoted Notch1 signaling and stemness characteristics in vitro and in vivo, as well as accelerating HCC initiation and tumor formation in the mouse xenograft tumor model. iNOS/NO led to Notch1 signaling through a pathway involving the soluble guanylyl cyclase/cGMP/PKG-dependent activation of TACE/ADAM17 and up-regulation of iRhom2 in LCSCs. In patients with HCC, higher TACE/ADAM17 expression and Notch1 activation correlated with poor prognosis. These findings link iNOS to Notch1 signaling in CD24+CD133+ LCSCs through the activation of TACE/ADAM17 and identify a mechanism for how iNOS contributes to progression of CD24+CD133+ HCC.
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43
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Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. Cancer Lett 2018; 433:165-175. [DOI: 10.1016/j.canlet.2018.06.040] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 01/02/2023]
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45
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Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, Silvola JMU, Roivainen A, Saraste A, Nickel AG, Saar JA, Sieve I, Pietzsch S, Müller M, Bogeski I, Kappl R, Jauhiainen M, Thackeray JT, Scherr M, Bengel FM, Hagl C, Tudorache I, Bauersachs J, Maack C, Hilfiker-Kleiner D. Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy. Eur Heart J 2018; 38:349-361. [PMID: 28201733 PMCID: PMC5381590 DOI: 10.1093/eurheartj/ehw086] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 12/01/2015] [Accepted: 12/13/2015] [Indexed: 12/19/2022] Open
Abstract
Aims The benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice. Methods and Results Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The β-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir. Conclusions Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.
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Affiliation(s)
- Britta Stapel
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Michael Kohlhaas
- Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany
| | - Melanie Ricke-Hoch
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Arash Haghikia
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Sergej Erschow
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Juhani Knuuti
- Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Johanna M U Silvola
- Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Anne Roivainen
- Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Antti Saraste
- Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Alexander G Nickel
- Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany
| | - Jasmin A Saar
- Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany
| | - Irina Sieve
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Stefan Pietzsch
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Mirco Müller
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Ivan Bogeski
- Department of Biophysics, CIPMM, School of Medicine, Saarland University, Homburg, Germany
| | - Reinhard Kappl
- Department of Biophysics, CIPMM, School of Medicine, Saarland University, Homburg, Germany
| | - Matti Jauhiainen
- Public Health Genomics Unit, National Institute for Health and Welfare, Genomics and Biomarkers Unit, Helsinki, Finland
| | - James T Thackeray
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Michaela Scherr
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany
| | - Frank M Bengel
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | | | - Igor Tudorache
- Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, MHH, Hannover, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
| | - Christoph Maack
- Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany
| | - Denise Hilfiker-Kleiner
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
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Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE. Cell Rep 2018; 21:745-757. [PMID: 29045841 PMCID: PMC5656746 DOI: 10.1016/j.celrep.2017.09.074] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 07/12/2017] [Accepted: 09/22/2017] [Indexed: 12/02/2022] Open
Abstract
Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage (“shedding”) of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents. Here, we report a role for iRhom2 in TACE stimulation on the cell surface. TACE shedding stimuli trigger MAP kinase-dependent phosphorylation of iRhom2 N-terminal cytoplasmic tail. This recruits 14-3-3 proteins, enforcing the dissociation of TACE from complexes with iRhom2, promoting the cleavage of TACE substrates. Our data reveal that iRhom2 controls multiple aspects of TACE biology, including stimulated shedding on the cell surface.
iRhom2 is phosphorylated in response to stimuli that activate the sheddase TACE Blocking iRhom phosphorylation represses TACE stimulated shedding Phosphorylated iRhom2 recruits 14-3-3 and dissociates from TACE, enabling shedding iRhom2 is thus a signal integrator and transducer of stimulated TACE shedding
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Muta Y, Fujita Y, Sumiyama K, Sakurai A, Taketo MM, Chiba T, Seno H, Aoki K, Matsuda M, Imajo M. Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine. Nat Commun 2018; 9:2174. [PMID: 29872037 PMCID: PMC5988836 DOI: 10.1038/s41467-018-04527-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 05/02/2018] [Indexed: 02/07/2023] Open
Abstract
Acting downstream of many growth factors, extracellular signal-regulated kinase (ERK) plays a pivotal role in regulating cell proliferation and tumorigenesis, where its spatiotemporal dynamics, as well as its strength, determine cellular responses. Here, we uncover the ERK activity dynamics in intestinal epithelial cells (IECs) and their association with tumour characteristics. Intravital imaging identifies two distinct modes of ERK activity, sustained and pulse-like activity, in IECs. The sustained and pulse-like activities depend on ErbB2 and EGFR, respectively. Notably, activation of Wnt signalling, the earliest event in intestinal tumorigenesis, augments EGFR signalling and increases the frequency of ERK activity pulses through controlling the expression of EGFR and its regulators, rendering IECs sensitive to EGFR inhibition. Furthermore, the increased pulse frequency is correlated with increased cell proliferation. Thus, ERK activity dynamics are defined by composite inputs from EGFR and ErbB2 signalling in IECs and their alterations might underlie tumour-specific sensitivity to pharmacological EGFR inhibition. The ERK signalling pathway regulates homeostasis of the intestinal epithelium. Here the authors identify two modes of ERK activity generated independently from EGFR and ErbB2 receptor and whose balance in cancer is shifted by Wnt pathway activation, resulting in enhanced sensitivity to EGFR inhibitors.
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Affiliation(s)
- Yu Muta
- Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, 606-8051, Japan.,Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Yoshihisa Fujita
- Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, 606-8501, Japan
| | - Kenta Sumiyama
- Laboratory for Mouse Genetic Engineering, Quantitative Biology Center, RIKEN, Osaka, 565-0874, Japan
| | - Atsuro Sakurai
- Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - M Mark Taketo
- Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.,Kansai Electric Power Hospital, Osaka, 553-0003, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan
| | - Kazuhiro Aoki
- Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan.,Department of Basic Biology, Faculty of Life Science, SOKENDAI (Graduate University for Advanced Studies), Myodaiji, Okazaki, Aichi, 444-8787, Japan
| | - Michiyuki Matsuda
- Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, 606-8051, Japan.,Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan
| | - Masamichi Imajo
- Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.
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Kreitman M, Noronha A, Yarden Y. Irreversible modifications of receptor tyrosine kinases. FEBS Lett 2018; 592:2199-2212. [PMID: 29790151 DOI: 10.1002/1873-3468.13095] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/12/2018] [Accepted: 05/08/2018] [Indexed: 01/18/2023]
Abstract
Each group of the 56 receptor tyrosine kinases (RTK) binds with one or more soluble growth factors and coordinates a vast array of cellular functions. These outcomes are tightly regulated by inducible post-translational events, such as tyrosine phosphorylation, ubiquitination, ectodomain shedding, and regulated intramembrane proteolysis. Because of the delicate balance required for appropriate RTK function, cells may become pathogenic upon dysregulation of RTKs themselves or their post-translational covalent modifications. For example, reduced ectodomain shedding and decreased ubiquitination of the cytoplasmic region, both of which enhance growth factor signals, characterize malignant cells. Whereas receptor phosphorylation and ubiquitination are reversible, proteolytic cleavage events are irreversible, and either modification might alter the subcellular localization of RTKs. Herein, we focus on ectodomain shedding by metalloproteinases (including ADAM family proteases), cleavage within the membrane or cytoplasmic regions of RTKs (by gamma-secretases and caspases, respectively), and complete receptor proteolysis in lysosomes and proteasomes. Roles of irreversible modifications in RTK signaling, pathogenesis, and pharmacology are highlighted.
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Affiliation(s)
- Matthew Kreitman
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Ashish Noronha
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
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Montero JC, Seoane S, García-Alonso S, Pandiella A. Multisite phosphorylation of P-Rex1 by protein kinase C. Oncotarget 2018; 7:77937-77949. [PMID: 27788493 PMCID: PMC5363633 DOI: 10.18632/oncotarget.12846] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 10/12/2016] [Indexed: 02/07/2023] Open
Abstract
P-Rex proteins are guanine nucleotide exchange factors (GEFs) that act on the Rho/Rac family of GTP binding proteins. The activity of P-Rex proteins is regulated by several extracellular stimuli. In fact, activation of growth factor receptors has been reported to activate a phosphorylation/dephosphorylation cycle of P-Rex1. Such cycle includes dephosphorylation of serines 313 and 319 which negatively regulate the GEF activity of P-Rex1, together with phosphorylation of serines 605 and 1169 which favour P-Rex1 GEF activity. However, the kinases that regulate phosphorylation at these different regulatory sites are largely unknown. Here we have investigated the potential regulatory action of several kinases on the phosphorylation of P-Rex1 at S313, S319, S605 and S1169. We show that activation of protein kinase C (PKC) caused phosphorylation of S313, S319 and S1169. Activation of growth factor receptors induced phosphorylation of S1169 through a mechanism that was independent of PKC, indicating that distinct kinases and mechanisms control the phosphorylation of P-Rex1 at different regulatory serines. Genetic and biochemical studies confirmed that the PKC isoform PKCδ was able to directly phosphorylate P-Rex1 at S313. Functional studies using cells with very low endogenous P-Rex1 expression, transfected with wild type P-Rex1 or a mutant form in which S313 was substituted by alanine, indicated that phosphorylation at that residue negatively regulated P-Rex1 exchange activity. We suggest that control of P-Rex1 activity depends on a highly dynamic interplay among distinct signalling routes and its multisite phosphorylation is controlled by the action of different kinases.
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Affiliation(s)
- Juan Carlos Montero
- Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain
| | - Samuel Seoane
- Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain
| | - Sara García-Alonso
- Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain
| | - Atanasio Pandiella
- Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain
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The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology. Mediators Inflamm 2018. [PMID: 29540993 PMCID: PMC5818912 DOI: 10.1155/2018/1067134] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated.
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