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Lu S, Chen Y, Song J, Ren L, Du J, Shen D, Peng J, Yin Y, Li X, Wang Y, Gao Y, Han S, Jia Y, Zhao Y, Wang Y. Cortisol regulates neonatal lung development via Smoothened. Respir Res 2025; 26:27. [PMID: 39827090 PMCID: PMC11743026 DOI: 10.1186/s12931-025-03104-0] [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: 08/21/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Neonatal respiratory distress syndrome (NRDS), one of the main causes of neonatal death, is clinically characterized by progressive dyspnea and cyanosis 1 to 2 h after birth. Corticosteroids are commonly used to prevent NRDS in clinical. However, the protective mechanism of the corticosteroids remains largely unclear. METHODS In this study, the simulation of the molecular docking by Autodock, in vitro binding experiments, and Sonic Hedgehog (SHH) pathway examination in cells were performed to study the directly binding of cortisol to Smoothened (SMO). To explore the effect of cortisol action on the SHH pathway on neonatal lung development, we generated a genetic mouse, in which leucine 116 (L112 in human) of SMO was mutated to alanine 116 (L116A, Smoa/a) by the CRISPR-Cas9, based on sequence differences between human and mice. Then, we performed morphological analysis, single-cell RNA sequencing (scRNA-seq) on lung tissue and fluorescence in situ hybridization (FISH). RESULTS In this study, we reported that cortisol, the endogenous glucocorticoid, inhibited the sonic hedgehog (Shh)/SMO-mediated proliferation of lung fibroblasts to maintain the normal lung development. Specifically, cortisol competed with cholesterol for binding to the cysteine-rich domain (CRD) in SMO to inhibit the activation of Shh/SMO signaling, a critical signaling known for cell proliferation. Cortisol did not inhibit the activation of SMO when L112 in its CRD was mutated to A112. Moreover, Smoa/a (L116A) mice exhibited the immature lungs in which over-proliferation of interstitial fibroblasts and reduction in the surfactant protein were evident. CONCLUSION Together, these results suggested that cortisol regulated cholesterol stimulation of SMO by competitively binding to the CRD to regulate neonatal lung maturation in mice.
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Affiliation(s)
- Shanshan Lu
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Yifei Chen
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Jiawen Song
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China
| | - Liangliang Ren
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Jun Du
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Donglai Shen
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Jiayin Peng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China
| | - Yao Yin
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Xia Li
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Yuqing Wang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Yan Gao
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Siman Han
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Yichang Jia
- Tsinghua-Peking Joint Center for Life Sciences, School of Medicine, Medical Science Building, Tsinghua University, Beijing, 100084, China
| | - Yun Zhao
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China.
| | - Yizheng Wang
- National Clinical Research Center for Aging and Medicine, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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Baguma-Nibasheka M, Kablar B. Mechanics of Lung Development. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2023; 236:131-150. [PMID: 37955774 DOI: 10.1007/978-3-031-38215-4_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
We summarize how skeletal muscle and lung developmental biology fields have been bridged to benefit from mouse genetic engineering technologies and to explore the role of fetal breathing-like movements (FBMs) in lung development, by using skeletal muscle-specific mutant mice. It has been known for a long time that FBMs are essential for the lung to develop properly. However, the cellular and molecular mechanisms transducing the mechanical forces of muscular activity into specific genetic programs that propel lung morphogenesis (development of the shape, form and size of the lung, its airways, and gas exchange surface) as well as its differentiation (acquisition of specialized cell structural and functional features from their progenitor cells) are only starting to be revealed. This chapter is a brief synopsis of the cumulative findings from that ongoing quest. An update on and the rationale for our recent International Mouse Phenotyping Consortium (IMPC) search is also provided.
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Affiliation(s)
- Mark Baguma-Nibasheka
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
| | - Boris Kablar
- Department of Medical Neuroscience, Anatomy and Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
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Consensus scoring-based virtual screening and molecular dynamics simulation of some TNF-alpha inhibitors. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2021.100833] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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Constitutive and Regulated Shedding of Soluble FGF Receptors Releases Biologically Active Inhibitors of FGF-2. Int J Mol Sci 2021; 22:ijms22052712. [PMID: 33800200 PMCID: PMC7962449 DOI: 10.3390/ijms22052712] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 12/03/2022] Open
Abstract
The identification of soluble fibroblast growth factor (FGF) receptors in blood and the extracellular matrix has led to the prediction that these proteins modulate the diverse biological activities of the FGF family of ligands in vivo. A recent structural characterization of the soluble FGF receptors revealed that they are primarily generated by proteolytic cleavage of the FGFR-1 ectodomain. Efforts to examine their biological properties are now focused on understanding the functional consequences of FGFR-1 ectodomain shedding and how the shedding event is regulated. We have purified an FGFR-1 ectodomain that is constitutively cleaved from the full-length FGFR-1(IIIc) receptor and released into conditioned media. This shed receptor binds FGF-2; inhibits FGF-2-induced cellular proliferation; and competes with high affinity, cell surface FGF receptors for ligand binding. FGFR-1 ectodomain shedding downregulates the number of high affinity receptors from the cell surface. The shedding mechanism is regulated by ligand binding and by activators of PKC, and the two signaling pathways appear to be independent of each other. Deletions and substitutions at the proposed cleavage site of FGFR-1 do not prevent ectodomain shedding. Broad spectrum inhibitors of matrix metalloproteases decrease FGFR-1 ectodomain shedding, suggesting that the enzyme responsible for constitutive, ligand-activated, and protein kinase C-activated shedding is a matrix metalloprotease. In summary, shedding of the FGFR-1 ectodomain is a highly regulated event, sharing many features with a common system that governs the release of diverse membrane proteins from the cell surface. Most importantly, the FGFR ectodomains are biologically active after shedding and are capable of functioning as inhibitors of FGF-2.
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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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Fang R, Haxaire C, Otero M, Lessard S, Weskamp G, McIlwain DR, Mak TW, Lichtenthaler SF, Blobel CP. Role of iRhoms 1 and 2 in Endochondral Ossification. Int J Mol Sci 2020; 21:ijms21228732. [PMID: 33227998 PMCID: PMC7699240 DOI: 10.3390/ijms21228732] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/10/2020] [Accepted: 11/12/2020] [Indexed: 12/18/2022] Open
Abstract
Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification.
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Affiliation(s)
- Renpeng Fang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China;
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USA; (C.H.); (G.W.)
| | - Coline Haxaire
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USA; (C.H.); (G.W.)
| | - Miguel Otero
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USA; (M.O.); (S.L.)
| | - Samantha Lessard
- Orthopedic Soft Tissue Research Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USA; (M.O.); (S.L.)
| | - Gisela Weskamp
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USA; (C.H.); (G.W.)
| | - David R. McIlwain
- Baxter Laboratory in Stem Cell Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Tak W. Mak
- Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada;
| | - Stefan F. Lichtenthaler
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany;
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany
- Institute for Advanced Study, Technische Universität München, 85748 Garching, Germany
| | - Carl P. Blobel
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USA; (C.H.); (G.W.)
- Institute for Advanced Study, Technische Universität München, 85748 Garching, Germany
- Department of Medicine, Department of Biophysics, Physiology and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA
- Correspondence: ; Tel.: +212-606-1429; Fax: +212-774-2560
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Sah RK, Ma J, Bah FB, Xing Z, Adlat S, Oo ZM, Wang Y, Bahadar N, Bohio AA, Nagi FH, Feng X, Zhang L, Zheng Y. Targeted Disruption of Mouse Dip2B Leads to Abnormal Lung Development and Prenatal Lethality. Int J Mol Sci 2020; 21:E8223. [PMID: 33153107 PMCID: PMC7663123 DOI: 10.3390/ijms21218223] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/21/2022] Open
Abstract
Molecular and anatomical functions of mammalian Dip2 family members (Dip2A, Dip2B and Dip2C) during organogenesis are largely unknown. Here, we explored the indispensable role of Dip2B in mouse lung development. Using a LacZ reporter, we explored Dip2B expression during embryogenesis. This study shows that Dip2B expression is widely distributed in various neuronal, myocardial, endothelial, and epithelial cell types during embryogenesis. Target disruption of Dip2b leads to intrauterine growth restriction, defective lung formation and perinatal mortality. Dip2B is crucial for late lung maturation rather than early-branching morphogenesis. The morphological analysis shows that Dip2b loss leads to disrupted air sac formation, interstitium septation and increased cellularity. In BrdU incorporation assay, it is shown that Dip2b loss results in increased cell proliferation at the saccular stage of lung development. RNA-seq analysis reveals that 1431 genes are affected in Dip2b deficient lungs at E18.5 gestation age. Gene ontology analysis indicates cell cycle-related genes are upregulated and immune system related genes are downregulated. KEGG analysis identifies oxidative phosphorylation as the most overrepresented pathways along with the G2/M phase transition pathway. Loss of Dip2b de-represses the expression of alveolar type I and type II molecular markers. Altogether, the study demonstrates an important role of Dip2B in lung maturation and survival.
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Affiliation(s)
- Rajiv Kumar Sah
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Jun Ma
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China;
| | - Fatoumata Binta Bah
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Zhenkai Xing
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Salah Adlat
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Zin Ma Oo
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Yajun Wang
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Noor Bahadar
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Ameer Ali Bohio
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Farooq Hayel Nagi
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Xuechao Feng
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
| | - Luqing Zhang
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
- Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA
| | - Yaowu Zheng
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (R.K.S.); (F.B.B.); (Z.X.); (S.A.); (Z.M.O.); (Y.W.); (N.B.); (A.A.B.); (F.H.N.); (L.Z.)
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Abstract
Proteolysis has emerged as a key post-translational regulator of the function of molecules on the cell surface and in the extracellular milieu. In principle, proteolysis can activate or inactivate a substrate, or can change its functional properties. ADAMs (a disintegrin and metalloprotease) and ADAMTS (a disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats) proteases are related members of a superfamily of metallo-endopeptidases that also includes MMPs and astacins. ADAMs are integral membrane proteins that typically cleave other membrane anchored proteins, whereas ADAMTS proteases lack a membrane anchor, and process both cell-surface and secreted molecules, the latter mostly extracellular matrix (ECM) components. ADAMs are implicated in fertilization, neurogenesis, in regulating the function of ligands for the EGF-receptor, and in the release of proteins such as the pro-inflammatory cytokine TNFα from the plasma membrane. ADAMTS proteases have key roles in embryonic development, including lung development, the molecular maturation of von Willebrand factor and procollagen as well as organization of fibrillin microfibrils in ECM, and are implicated in the pathogenesis of diverse lung and airway disorders. Here, we provide a general overview of the biochemical properties and physiological functions of ADAMs and ADAMTS proteases and describe their relevance to lung and airway disorders.
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Mesenchyme-specific deletion of Tgf-β1 in the embryonic lung disrupts branching morphogenesis and induces lung hypoplasia. J Transl Med 2019; 99:1363-1375. [PMID: 31028279 PMCID: PMC7422700 DOI: 10.1038/s41374-019-0256-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/06/2019] [Accepted: 03/13/2019] [Indexed: 01/08/2023] Open
Abstract
Proper lung development depends on the precise temporal and spatial expression of several morphogenic factors, including Fgf10, Fgf9, Shh, Bmp4, and Tgf-β. Over- or under-expression of these molecules often leads to aberrant embryonic or postnatal lung development. Herein, we deleted the Tgf-β1 gene specifically within the lung embryonic mesenchymal compartment at specific gestational stages to determine the contribution of this cytokine to lung development. Mutant embryos developed severe lung hypoplasia and died at birth due to the inability to breathe. Despite the markedly reduced lung size, proliferation and differentiation of the lung epithelium was not affected by the lack of mesenchymal expression of the Tgf-β1 gene, while apoptosis was significantly increased in the mutant lung parenchyma. Lack of mesenchymal expression of the Tgf-β1 gene was also associated with reduced lung branching morphogenesis, with accompanying inhibition of the local FGF10 signaling pathway as well as abnormal development of the vascular system. To shed light on the mechanism of lung hypoplasia, we quantified the phosphorylation of 226 proteins in the mutant E12.5 lung compared with control. We identified five proteins, Hrs, Vav2, c-Kit, the regulatory subunit of Pi3k (P85), and Fgfr1, that were over- or under-phosphorylated in the mutant lung, suggesting that they could be indispensable effectors of the TGF-β signaling program during embryonic lung development. In conclusion, we have uncovered novel roles of the mesenchyme-specific Tgf-β1 ligand in embryonic mouse lung development and generated a mouse model that may prove helpful to identify some of the key pathogenic mechanisms underlying lung hypoplasia in humans.
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Rare mutations of ADAM17 from TOFs induce hypertrophy in human embryonic stem cell-derived cardiomyocytes via HB-EGF signaling. Clin Sci (Lond) 2019; 133:225-238. [PMID: 30610007 PMCID: PMC6365624 DOI: 10.1042/cs20180842] [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: 09/26/2018] [Revised: 12/22/2018] [Accepted: 01/03/2019] [Indexed: 12/31/2022]
Abstract
Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart defects (CHDs). The right ventricular hypertrophy is associated with the survival rate of patients with repaired TOF. However, very little is known concerning its genetic etiology. Based on mouse model studies, a disintergrin and metalloprotease 10/17 (ADAM10 and ADAM17) are the key enzymes for the NOTCH and ErbB pathways, which are critical pathways for heart development. Mutations in these two genes have not been previously reported in human TOF patients. In this study, we sequenced ADAM10 and ADAM17 in a Han Chinese CHD cohort comprised of 80 TOF patients, 286 other CHD patients, and 480 matched healthy controls. Three missense variants of ADAM17 were only identified in 80 TOF patients, two of which (Y42D and L659P) are novel and not found in the Exome Aggregation Consortium (ExAC) database. Point mutation knock-in (KI) and ADAM17 knock-out (KO) human embryonic stem cells (hESCs) were generated by CRISPR/Cas9 and programmed to differentiate into cardiomyocytes (CMs). Y42D or L659P KI cells or complete KO cells all developed hypertrophy with disorganized sarcomeres. RNA-seq results showed that phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), which is downstream of epidermal growth factor receptor (EGFR) signaling, was affected in both ADAM17 KO and KI hESC-CMs. In vitro experiments showed that these two mutations are loss-of-function mutations in shedding heparin-binding EGF-like growth factor (HB-EGF) but not NOTCH signaling. Our results revealed that CM hypertrophy in TOF could be the result of mutations in ADAM17 which affects HB-EGF/ErbB signaling.
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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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Stark A, Dammann C, Nielsen HC, Volpe MV. A Pathogenic Relationship of Bronchopulmonary Dysplasia and Retinopathy of Prematurity? A Review of Angiogenic Mediators in Both Diseases. Front Pediatr 2018; 6:125. [PMID: 29951473 PMCID: PMC6008318 DOI: 10.3389/fped.2018.00125] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 04/16/2018] [Indexed: 01/11/2023] Open
Abstract
Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are common and significant morbidities of prematurely born infants. These diseases have in common altered and pathologic vascular formation in the face of incomplete organ development. Therefore, it is reasonable to question whether factors affecting angiogenesis could have a joint pathogenic role for both diseases. Inhibition or induced expression of a single angiogenic factor is unlikely to be 100% causative or protective of either of BPD or ROP. It is more likely that interactions of multiple factors leading to disordered angiogenesis are present, increasing the likelihood of common pathways in both diseases. This review explores this possibility by assessing the evidence showing involvement of specific angiogenic factors in the vascular development and maldevelopment in each disease. Theoretical interactions of specific factors mutually contributing to BPD and ROP are proposed and, where possible, a timeline of the proposed relationships between BPD and ROP is developed. It is hoped that future research will be inspired by the theories put forth in this review to enhance the understanding of the pathogenesis in both diseases.
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Affiliation(s)
- Ashley Stark
- Tufts University School of Medicine, Boston, MA, United States
| | - Christiane Dammann
- Tufts University School of Medicine, Boston, MA, United States.,Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, MA, United States.,Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States
| | - Heber C Nielsen
- Tufts University School of Medicine, Boston, MA, United States.,Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, MA, United States.,Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, United States
| | - MaryAnn V Volpe
- Tufts University School of Medicine, Boston, MA, United States.,Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, MA, United States
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Fujioka K, Kalish F, Zhao H, Lu S, Wong S, Wong RJ, Stevenson DK. Induction of Heme Oxygenase-1 Attenuates the Severity of Sepsis in a Non-Surgical Preterm Mouse Model. Shock 2017; 47:242-250. [PMID: 27454382 DOI: 10.1097/shk.0000000000000689] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Preterm sepsis is characterized by systemic bacterial invasion and inflammatory response. Its pathogenesis is unclear due to lack of proper animal models. Heme oxygenase-1 (HO-1) can affect physiologic and pathologic conditions through its anti-inflammatory, antioxidative, and anti-apoptotic properties. Since HO-1 is developmentally regulated, it may play a role in the pathogenesis of preterm sepsis. For this study, sepsis was induced using the non-surgical "cecal slurry" (CS) model. CS was given intraperitoneally at various doses to 4-day-old newborn mice to determine dose-dependent effects. The LD40 was then given and changes in bodyweight, bacterial colonization of organs, hematology, serum biochemistry, and immunomodulatory gene expression were determined. We found a dose-dependent mortality with an LD40 of 2.0 mg/g. Significant bacterial colonization and hematological changes (leukocytopenia, thrombocytopenia, and lymphocytopenia) and increased gene expression of pro-inflammatory cytokines, pattern-recognition receptors, and other genes related to immune responses were also observed. Twenty-four hours post-sepsis induction, bodyweight loss was associated with mortality and organ damage. Finally, to elucidate a protective role of HO-1, 30-μmol heme/kg was given subcutaneously 24 h pre-sepsis induction. HO activity in livers and spleens significantly increased 64% and 50% over age-matched controls 24 h post-heme administration. Importantly, heme significantly reduced mortality from 40.9% to 6.3% (P <0.005) and gene expression of pro-inflammatory cytokines (Ccl5, Cxcl10, IL-1b, and Ifng). We conclude that the CS model can be used as a model to study preterm sepsis. Because induction of HO-1 significantly reduced mortality, we speculate that HO-1 may confer protection against sepsis in preterm infants.
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Affiliation(s)
- Kazumichi Fujioka
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, California
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Kemp MW, Saito M, Usuda H, Molloy TJ, Miura Y, Sato S, Watanabe S, Clarke M, Fossler M, Scmidt A, Kallapur SG, Kramer BW, Newnham JP, Jobe AH. Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate. Am J Obstet Gynecol 2016; 215:775.e1-775.e12. [PMID: 27555319 DOI: 10.1016/j.ajog.2016.08.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/24/2016] [Accepted: 08/10/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Antenatal steroids are standard of care for cases of anticipated preterm labor to improve neonatal outcomes. However, steroids are potent drugs, and their use in pregnancy remains largely unoptimized. OBJECTIVE The objective of the study was to measure the maternofetal pharmacokinetics of constant, low-dose intravenous betamethasone phosphate infusions and correlate these data with the transcriptional effect exerted by subclinical betamethasone exposures on the ovine fetal lung. STUDY DESIGN Thirty-two ewes carrying a single fetus had surgery to catheterize fetal and maternal jugular veins at 116 days of gestation (term, 150 days). Animals were recovered for 2 days and then were randomized to receive 2 sequential maternal intravenous infusions of either (n = 4/group) of the following: 1) saline, 0.125, 0.04, or 0.0125 mg/kg betamethasone phosphate over 3 hours; or 2) saline, 0.25, 0.08, or 0.025 mg/kg betamethasone phosphate over 12 hours. Each infusion was separated by 2 days. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction and an ovine-specific microarray. Plasma betamethasone levels from time-course catheter samples were determined by mass spectrometry. Data were assessed for distribution, variance, and tested by an analysis of variance. RESULTS Betamethasone was detectable (>1 ng/mL) in fetal plasma only in animals randomized to 0.125 mg/kg 3 hour or 0.250 mg/kg 12 hour infusions. Fetal betamethasone half-lives were 1.7-2.8 times greater than maternal values. At maximum concentration, fetal plasma betamethasone levels were approximately 10% of maternal levels. Compared with saline control, all animals, other than those receiving 0.0125 mg/kg 3 hour betamethasone phosphate infusions, had evidence of dose-dependent glucocorticoid transcriptional responses in the fetal lung. CONCLUSION Constant maternal betamethasone infusions delivering substantially lower fetal and maternal betamethasone maximal concentrations than those achieved with current clinical treatment protocols were associated with dose-dependent changes in glucocorticoid-response markers in the fetal lung. Further studies to determine the minimally efficacious dose of steroids for improving outcomes in preterm infants should be viewed as a priority.
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Aghababaei M, Beristain AG. The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: a focus on ADAM12. Placenta 2015; 36 Suppl 1:S11-9. [PMID: 25589360 DOI: 10.1016/j.placenta.2014.12.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 12/04/2014] [Accepted: 12/17/2014] [Indexed: 10/25/2022]
Abstract
Placental development is a highly regulated process requiring signals from both fetal and maternal uterine compartments. Within this complex system, trophoblasts, placental cells of epithelial lineage, form the maternal-fetal interface controlling nutrient, gas and waste exchange. The commitment of progenitor villous cytotrophoblasts to differentiate into diverse trophoblast subsets is a fundamental process in placental development. Differentiation of trophoblasts into invasive stromal- and vascular-remodeling subtypes is essential for uterine arterial remodeling and placental function. Inadequate placentation, characterized by defects in trophoblast differentiation, may underlie the earliest cellular events driving pregnancy disorders such as preeclampsia and fetal growth restriction. Molecularly, invasive trophoblasts acquire characteristics defined by profound alterations in cell-cell and cell-matrix adhesion, cytoskeletal reorganization and production of proteolytic factors. To date, most studies have investigated the importance of the matrix metalloproteinases (MMPs) and their ability to efficiently remodel components of the extracellular matrix (ECM). However, it is now becoming clear that besides MMPs, other related proteases regulate trophoblast invasion via mechanisms other than ECM turnover. In this review, we will summarize the current knowledge on the regulation of trophoblast invasion by members of the metzincin family of metalloproteinases. Specifically, we will discuss the emerging roles that A Disintegrin and Metalloproteinases (ADAMs) play in placental development, with a particular focus on the ADAM subtype, ADAM12.
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Affiliation(s)
- Mahroo Aghababaei
- Department of Obstetrics and Gynecology, The University of British Columbia, Canada; The Child and Family Research Institute, Vancouver, Canada
| | - Alexander G Beristain
- Department of Obstetrics and Gynecology, The University of British Columbia, Canada; The Child and Family Research Institute, Vancouver, Canada.
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Dreymueller D, Uhlig S, Ludwig A. ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets. Am J Physiol Lung Cell Mol Physiol 2014; 308:L325-43. [PMID: 25480335 DOI: 10.1152/ajplung.00294.2014] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Acute and chronic lung inflammation is driven and controlled by several endogenous mediators that undergo proteolytic conversion from surface-expressed proteins to soluble variants by a disintegrin and metalloproteinase (ADAM)-family members. TNF and epidermal growth factor receptor ligands are just some of the many substrates by which these proteases regulate inflammatory or regenerative processes in the lung. ADAM10 and ADAM17 are the most prominent members of this protease family. They are constitutively expressed in most lung cells and, as recent research has shown, are the pivotal shedding enzymes mediating acute lung inflammation in a cell-specific manner. ADAM17 promotes endothelial and epithelial permeability, transendothelial leukocyte migration, and inflammatory mediator production by smooth muscle and epithelial cells. ADAM10 is critical for leukocyte migration and alveolar leukocyte recruitment. ADAM10 also promotes allergic asthma by driving B cell responses. Additionally, ADAM10 acts as a receptor for Staphylococcus aureus (S. aureus) α-toxin and is crucial for bacterial virulence. ADAM8, ADAM9, ADAM15, and ADAM33 are upregulated during acute or chronic lung inflammation, and recent functional or genetic analyses have linked them to disease development. Pharmacological inhibitors that allow us to locally or systemically target and differentiate ADAM-family members in the lung suppress acute and asthmatic inflammatory responses and S. aureus virulence. These promising results encourage further research to develop therapeutic strategies based on selected ADAMs. These studies need also to address the role of the ADAMs in repair and regeneration in the lung to identify further therapeutic opportunities and possible side effects.
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Affiliation(s)
- Daniela Dreymueller
- Institute of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | - Stefan Uhlig
- Institute of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | - Andreas Ludwig
- Institute of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
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Marcelino MY, Fuoco NL, de Faria CA, Kozma RDLH, Marques LF, Ribeiro-Paes JT. Animal models in chronic obstructive pulmonary disease-an overview. Exp Lung Res 2014; 40:259-71. [PMID: 24785359 DOI: 10.3109/01902148.2014.908250] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction resultant from an augmented inflammatory response of the respiratory tract to noxious particles and gases. Previous reports present a number of different hypotheses about the etiology and pathophysiology of COPD. The generating mechanisms of the disease are subject of much speculation, and a series of questions and controversies among experts still remain. In this context, several experimental models have been proposed in order to broaden the knowledge on the pathophysiological characteristics of the disease, as well as the search for new therapeutic approaches for acute or chronically injured lung tissue. This review aims to present the main experimental models of COPD, more specifically emphysema, as well as to describe the main characteristics, advantages, disadvantages, possibilities of application, and potential contribution of each of these models for the knowledge on the pathophysiological aspects and to test new treatment options for obstructive lung diseases.
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Affiliation(s)
- Monica Yonashiro Marcelino
- 1Program of Post-Graduation in Biotechnology, Universidade de São Paulo-Instituto Butantan, São Paulo, São Paulo, Brazil
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Dissociated presenilin-1 and TACE processing of ErbB4 in lung alveolar type II cell differentiation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2014; 1843:797-805. [PMID: 24462774 DOI: 10.1016/j.bbamcr.2014.01.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 12/18/2013] [Accepted: 01/13/2014] [Indexed: 01/25/2023]
Abstract
Neuregulin (NRG) stimulation of ErbB4 signaling is important for type II cell surfactant synthesis. ErbB4 may mediate gene expression via a non-canonical pathway involving enzymatic cleavage releasing its intracellular domain (4ICD) for nuclear trafficking and gene regulation. The accepted model for release of 4ICD is consecutive cleavage by Tumor necrosis factor alpha Converting Enzyme (TACE) and γ-secretase enzymes. Here, we show that 4ICD mediates surfactant synthesis and its release by γ-secretase is not dependent on previous TACE cleavage. We used siRNA to silence Presenilin-1 (PSEN-1) expression in a mouse lung type II epithelial cell line (MLE12 cells), and both siRNA knockdown and chemical inhibition of TACE. Knockdown of PSEN-1 significantly decreased baseline and NRG-stimulated surfactant phospholipid synthesis, expression of the surfactant proteins SP-B and SP-C, as well as 4ICD levels, with no change in ErbB4 ectodomain shedding. Neither siRNA knockdown nor chemical inhibition of TACE inhibited 4ICD release or surfactant synthesis. PSEN-1 cleavage of ErbB4 for non-canonical signaling through 4ICD release does not require prior cleavage by TACE.
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Xu W, Liu C, Kaartinen V, Chen H, Lu CH, Zhang W, Luo Y, Shi W. TACE in perinatal mouse lung epithelial cells promotes lung saccular formation. Am J Physiol Lung Cell Mol Physiol 2013; 305:L953-63. [PMID: 24142516 DOI: 10.1152/ajplung.00189.2013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Tumor necrosis factor-α converting enzyme (TACE) is a cell membrane sheddase, expressed in both developmental lung epithelia and mesenchyme. Global abrogation of TACE results in neonatal lethality and multiple organ developmental abnormalities, including dysplastic lung. To further define the roles of TACE in regulating lung development, lung epithelial and/or mesenchymal specific TACE conditional knockout mice were generated. Blockade of TACE function in developing lung epithelial cells caused reduced saccular formation, decreased cell proliferation, and reduced mid-distal lung epithelial cell differentiation. In contrast, mesenchymal TACE knockout did not have any phenotypic change in developing lung. Simultaneous abrogation of TACE in both lung epithelial and mesenchymal cells did not result in a more severe lung abnormality. Interestingly, these lung-specific TACE conditional knockout mice were not neonatal lethal, and their lung structures were essentially normal after alveolarization. In addition, TACE conditional knockout in developing cardiomyocytes resulted in noncompaction of ventricular myocardium, as seen in TACE conventional knockout mice. However, these mice were also not neonatal lethal. In conclusion, lung epithelial TACE is essential for promoting fetal lung saccular formation, but not postnatal lung alveolarization in mice. Because the developmental abnormality of either lung or heart induced by TACE deficiency does not directly lead to neonatal lethality, the neonatal death of TACE conventional knockout mice is likely a result of synergistic effects of multiple organ abnormalities.
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Affiliation(s)
- Wei Xu
- Developmental Biology and Regenerative Medicine Program, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop 35, Los Angeles, CA 90027.
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20
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Wang Y, Huang Z, Nayak PS, Matthews BD, Warburton D, Shi W, Sanchez-Esteban J. Strain-induced differentiation of fetal type II epithelial cells is mediated via the integrin α6β1-ADAM17/tumor necrosis factor-α-converting enzyme (TACE) signaling pathway. J Biol Chem 2013; 288:25646-25657. [PMID: 23888051 DOI: 10.1074/jbc.m113.473777] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Mechanical forces are critical for normal fetal lung development. However, the mechanisms regulating this process are not well-characterized. We hypothesized that strain-induced release of HB-EGF and TGF-α is mediated via integrin-ADAM17/TACE interactions. Employing an in vitro system to simulate mechanical forces in fetal lung development, we showed that mechanical strain of fetal epithelial cells actives TACE, releases HB-EGF and TGF-α, and promotes differentiation. In contrast, in samples incubated with the TACE inhibitor IC-3 or in cells isolated from TACE knock-out mice, mechanical strain did not release ligands or promote cell differentiation, which were both rescued after transfection of ADAM17. Cell adhesion assay and co-immunoprecipitation experiments in wild-type and TACE knock-out cells using several TACE constructs demonstrated not only that integrins α6 and β1 bind to TACE via the disintegrin domain but also that mechanical strain enhances these interactions. Furthermore, force applied to these integrin receptors by magnetic beads activated TACE and shed HB-EGF and TGF-α. The contribution of integrins α6 and β1 to differentiation of fetal epithelial cells by strain was demonstrated by blocking their binding site with specific antibodies and by culturing the cells on membranes coated with anti-integrin α6 and β1 antibodies. In conclusion, mechanical strain releases HB-EGF and TGF-α and promotes fetal type II cell differentiation via α6β1 integrin-ADAM17/TACE signaling pathway. These investigations provide novel mechanistic information on how mechanical forces promote fetal lung development and specifically differentiation of epithelial cells. This information could be also relevant to other tissues exposed to mechanical forces.
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Affiliation(s)
- Yulian Wang
- From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905
| | - Zheping Huang
- From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905
| | - Pritha S Nayak
- From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905
| | - Benjamin D Matthews
- the Vascular Biology Program, Departments of Medicine, Pathology, and Surgery, Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts 02115, and
| | - David Warburton
- the Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027
| | - Wei Shi
- the Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027
| | - Juan Sanchez-Esteban
- From the Department of Pediatrics, Women & Infants Hospital of Rhode Island and the Warren Alpert Medical School, Brown University, Providence, Rhode Island 02905,.
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21
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ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes. Mol Cell Biol 2013. [PMID: 23732913 DOI: 10.1128/mcb.00291‐13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.
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22
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ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes. Mol Cell Biol 2013; 33:3077-90. [PMID: 23732913 DOI: 10.1128/mcb.00291-13] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.
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ADAM17 is critical for multipolar exit and radial migration of neuronal intermediate progenitor cells in mice cerebral cortex. PLoS One 2013; 8:e65703. [PMID: 23755270 PMCID: PMC3670835 DOI: 10.1371/journal.pone.0065703] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2012] [Accepted: 05/02/2013] [Indexed: 01/24/2023] Open
Abstract
The radial migration of neuronal progenitor cells is critical for the development of cerebral cortex layers. They go through a critical step transforming from multipolar to bipolar before outward migration. A Disintegrin and Metalloprotease 17 (ADAM17) is a transmembrane protease which can process many substrates involved in cell-cell interaction, including Notch, ligands of EGFR, and some cell adhesion molecules. In this study, we used in utero electroporation to knock down or overexpress ADAM17 at embryonic day 14.5 (E14.5) in neuronal progenitor cells to examine the role of ADAM17 in cortical embryonic neurogenesis. Our results showed that the radial migration of ADAM17-knocked down cells were normal till E16.5 and reached the intermediate zone (IZ). Then most transfected cells stopped migration and stayed at the IZ to inner cortical plate (CP) layer at E18.5, and there was higher percentage of multipolar cells at IZ layer in the ADAM17-knocked down group compared to the cells in control group. Marker staining revealed that those ADAM17-knocked down cells differentiated normally from neural stem cells (NSCs) to neuronal intermediate progenitor cells (nIPCs) but did not differentiate into mature neurons. The migration and multipolar exit defects caused by ADAM17 knockdown could be partially rescued by over-expressing an shRNA resistant ADAM17, while overexpressing ADAM17 alone did not affect the radial migration. Taken together, our results showed for the first time that, ADAM17 is critical in regulating the multipolar-stage exit and radial migration of the nIPCs during telencephalon cortex development in mice.
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Lin J, Yan X, Wang C, Talabattula VAN, Guo Z, Rolfs A, Luo J. Expression patterns of the ADAMs in early developing chicken cochlea. Dev Growth Differ 2013; 55:368-76. [PMID: 23496030 DOI: 10.1111/dgd.12051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/29/2013] [Accepted: 02/04/2013] [Indexed: 12/30/2022]
Abstract
Members of the ADAM (a disintegrin and metalloprotease) family are type I transmembrane proteins involved in biological processes of proteolysis, cell adhesion, cell-matrix interaction, as well as in the intracellular signaling transduction. In the present study, expression patterns of seven members of the ADAM family were investigated at the early stages of the developing cochlea by in situ hybridization. The results show that each individual ADAM is expressed and regulated in the early developing cochlea. ADAM9, ADAM10, ADAM17, and ADAM23 are initially and widely expressed in the otic vesicle at embryonic day 2.5 (E2.5) and in the differential elements of the cochlear duct at E9, while ADAM12 is expressed in acoustic ganglion cells at E7. ADAM22 is detectable in cochlear ganglion cells as early as from E4 and in the basilar papilla from E7. Therefore, the present study extends our previous results and suggests that ADAMs also play a role in the early cochlear development.
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Affiliation(s)
- Juntang Lin
- Key Laboratory for Medical Tissue Regeneration of Henan Province, Xinxiang Medical University, Xinxiang City, 453003, Henan, China
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25
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Wilson CL, Gough PJ, Chang CA, Chan CK, Frey JM, Liu Y, Braun KR, Chin MT, Wight TN, Raines EW. Endothelial deletion of ADAM17 in mice results in defective remodeling of the semilunar valves and cardiac dysfunction in adults. Mech Dev 2013; 130:272-89. [PMID: 23354118 DOI: 10.1016/j.mod.2013.01.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 12/21/2012] [Accepted: 01/07/2013] [Indexed: 12/24/2022]
Abstract
Global inactivation of the metalloproteinase ADAM17 during mouse development results in perinatal lethality and abnormalities of the heart, including late embryonic cardiomegaly and thickened semilunar and atrioventricular valves. These defects have been attributed in part to a lack of ADAM17-mediated processing of HB-EGF, as absence of soluble HB-EGF results in similar phenotypes. Because valvular mesenchymal cells are largely derived from cardiac endothelial cells, we generated mice with a floxed Adam17 allele and crossed these animals with Tie2-Cre transgenics to focus on the role of endothelial ADAM17 in valvulogenesis. We find that although hearts from late-stage embryos with ablation of endothelial ADAM17 appear normal, an increase in valve size and cell number is evident, but only in the semilunar cusps. Unlike Hbegf(-/-) valves, ADAM17-null semilunar valves do not differ from controls in acute cell proliferation at embryonic day 14.5 (E14.5), suggesting compensatory processing of HB-EGF. However, levels of the proteoglycan versican are significantly reduced in mutant hearts early in valve remodeling (E12.5). After birth, aortic valve cusps from mutants are not only hyperplastic but also show expansion of the glycosaminoglycan-rich component, with the majority of adults exhibiting aberrant compartmentalization of versican and increased deposition of collagen. The inability of mutant outflow valve precursors to transition into fully mature cusps is associated with decreased postnatal viability, progressive cardiomegaly, and systolic dysfunction. Together, our data indicate that ADAM17 is required in valvular endothelial cells for regulating cell content as well as extracellular matrix composition and organization in semilunar valve remodeling and homeostasis.
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Affiliation(s)
- Carole L Wilson
- Department of Pathology, University of Washington, Seattle, WA 98104, USA.
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Xu K, Liang X, Shen K, Sun L, Cui D, Zhao Y, Tian J, Ni L, Liu J. MiR-222 modulates multidrug resistance in human colorectal carcinoma by down-regulating ADAM-17. Exp Cell Res 2012; 318:2168-77. [PMID: 22677042 DOI: 10.1016/j.yexcr.2012.04.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 04/10/2012] [Accepted: 04/13/2012] [Indexed: 12/15/2022]
Abstract
Colorectal carcinoma is a frequent cause of cancer-related death in men and women throughout the world. MicroRNAs are endogenous small noncoding RNAs that negatively regulate gene expression at the posttranscriptional level. We investigated the role of ADAM-17 (a desintegrin and metalloproteases 17) as a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC) and the role of miR-222 in the development of MDR in CRC cells. We found that the high expression of ADAM-17, which results in growth factor shedding and growth factor receptor activation could induce drug resistance in CRC. Pharmacological inhibition of ADAM-17, in conjunction with chemotherapy, may have therapeutic potential for the treatment of CRC. ADAM-17 is a predicted target of miR-222, which was downregulated in multidrug-resistant CRC cells. The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. We found that elevated levels of miR-222 in the mimics-transfected HCT116/L-OHP and HCT-8/VCR cells reduced the ADAM-17 protein level and the luciferase activity of an ADAM-17 3' untranslated region-based reporter and sensitized these cells' apoptosis to some anticancer drugs. Our findings suggest that miR-222 could play a role in the development of MDR by modulation of ADAM-17, the new MDR treatment target in colorectal carcinoma cells.
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Affiliation(s)
- Ke Xu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of pharmacy, East China University of Science and Technology, Shanghai, PR China
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Li X, Pérez L, Fan H. Inhibitory role of TACE/ADAM17 cytotail in protein ectodomain shedding. World J Biol Chem 2011; 2:246-51. [PMID: 22125668 PMCID: PMC3224872 DOI: 10.4331/wjbc.v2.i11.246] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Revised: 10/12/2011] [Accepted: 10/19/2011] [Indexed: 02/05/2023] Open
Abstract
AIM: To determine if the cytotail of the principal sheddase tumor necrosis factor-α converting enzyme (TACE; ADAM17) controls protein ectodomain shedding.
METHODS: Site-directed mutagenesis was performed to derive TACE variants. The resulting TACE expression plasmids with amino acid substitutions in the extracellular, cysteine-rich disintegrin domain (CRD) and/or deleted cytotail, along with an expression vector for the enhanced green fluorescence protein were transfected into shedding-defective M1 mutants stably expressing transmembrane L-selectin or transforming growth factor (TGF)-α. The expression levels of the TACE substrates at the cell surface were determined by flow cytometry.
RESULTS: Consistent with published data, a single point mutation (C600Y) in the CRD led to shedding deficiency. However, removal of the cytotail from the C600Y TACE variant partially restored ectodomain cleavage of TGF-α and L-selectin. Cytotail-deleted mutants with any other substituting amino acid residues in place of Cys600 displayed similar function compared with tail-less C600Y TACE.
CONCLUSION: The cytotail plays an inhibitory role, which becomes evident when it is removed from an enzyme with another mutation that affects the enzyme function.
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Affiliation(s)
- Xiaojin Li
- Xiaojin Li, Liliana Pérez, Huizhou Fan, Department of Physiology and Biophysics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, United States
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Duffy MJ, Mullooly M, O'Donovan N, Sukor S, Crown J, Pierce A, McGowan PM. The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer? Clin Proteomics 2011; 8:9. [PMID: 21906355 PMCID: PMC3170276 DOI: 10.1186/1559-0275-8-9] [Citation(s) in RCA: 153] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 06/09/2011] [Indexed: 12/14/2022] Open
Abstract
The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER/EGFR ligands. The released ligands activate HER/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer.
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Affiliation(s)
- Michael J Duffy
- Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin 4, Ireland
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
| | - Maeve Mullooly
- Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin 4, Ireland
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
| | - Norma O'Donovan
- National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Sumainizah Sukor
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
- Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland
| | - John Crown
- Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland
| | - Aisling Pierce
- Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin 4, Ireland
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
| | - Patricia M McGowan
- Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, Dublin 4, Ireland
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland
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29
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Zhang C, Tian L, Chi C, Wu X, Yang X, Han M, Xu T, Zhuang Y, Deng K. Adam10 is essential for early embryonic cardiovascular development. Dev Dyn 2011; 239:2594-602. [PMID: 20803506 DOI: 10.1002/dvdy.22391] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Notch pathway has been demonstrated to regulate cardiovascular development. One important step in Notch pathway is the cleavage of Notch receptor, during which an intracellular fragment of Notch protein is released to activate downstream genes. It is still uncertain whether Adam10, the mammalian homologue of Kuzbanian in Drosophila, is required to activate the Notch pathway during cardiovascular development. To further understand the physiological function of Adam10 in vascular and cardiac development, we generated mice lacking the Adam10 gene primarily in the endothelial compartment. We found that disruption of Adam10 in endothelial cells resulted in embryonic death after embryonic day 10.5 due to multiple cardiac and vascular defects similar to Notch1 mutants. We further showed that the expression of Notch target genes Snail and Bmp2 are impaired in Adam10-deficient cardiac tissues. Finally, we provide experimental evidence to support that Adam10 functions in a cell autonomous manner during mammalian cardiac development.
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Affiliation(s)
- Chi Zhang
- Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China
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30
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Hayashida K, Bartlett AH, Chen Y, Park PW. Molecular and cellular mechanisms of ectodomain shedding. Anat Rec (Hoboken) 2010; 293:925-37. [PMID: 20503387 DOI: 10.1002/ar.20757] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The extracellular domain of several membrane-anchored proteins is released from the cell surface as soluble proteins through a regulated proteolytic mechanism called ectodomain shedding. Cells use ectodomain shedding to actively regulate the expression and function of surface molecules, and modulate a wide variety of cellular and physiological processes. Ectodomain shedding rapidly converts membrane-associated proteins into soluble effectors and, at the same time, rapidly reduces the level of cell surface expression. For some proteins, ectodomain shedding is also a prerequisite for intramembrane proteolysis, which liberates the cytoplasmic domain of the affected molecule and associated signaling factors to regulate transcription. Ectodomain shedding is a process that is highly regulated by specific agonists, antagonists, and intracellular signaling pathways. Moreover, only about 2% of cell surface proteins are released from the surface by ectodomain shedding, indicating that cells selectively shed their protein ectodomains. This review will describe the molecular and cellular mechanisms of ectodomain shedding, and discuss its major functions in lung development and disease.
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Affiliation(s)
- Kazutaka Hayashida
- Division of Respiratory Diseases, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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31
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Shiomi T, Tschumperlin DJ, Park JA, Sunnarborg SW, Horiuchi K, Blobel CP, Drazen JM. TNF-α-converting enzyme/a disintegrin and metalloprotease-17 mediates mechanotransduction in murine tracheal epithelial cells. Am J Respir Cell Mol Biol 2010; 45:376-85. [PMID: 21097655 DOI: 10.1165/rcmb.2010-0234oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Bronchoconstriction applies compressive stress to airway epithelial cells. We show that the application of compressive stress to cultured murine tracheal epithelial cells elicits the increased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt through an epidermal growth factor receptor (EGFR)-dependent process, consistent with previous observations of the bronchoconstriction-induced activation of EGFR in both human and murine airways. Mechanotransduction requires metalloprotease activity, indicating a pivotal role for proteolytic EGF-family ligand shedding. However, cells derived from mice with targeted deletions of the EGFR ligands Tgfα and Hb-egf showed only modest decreases in responses, even when combined with neutralizing antibodies to the EGFR ligands epiregulin and amphiregulin, suggesting redundant or compensatory roles for individual EGF family members in mechanotransduction. In contrast, cells harvested from mice with a conditional deletion of the gene encoding the TNF-α-converting enzyme (TACE/ADAM17), a sheddase for multiple EGF-family proligands, displayed a near-complete attenuation of ERK and Akt phosphorylation responses and compressive stress-induced gene regulation. Our data provide strong evidence that TACE plays a critical central role in the transduction of compressive stress.
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Affiliation(s)
- Tetsuya Shiomi
- Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA
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32
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Rivera S, Khrestchatisky M, Kaczmarek L, Rosenberg GA, Jaworski DM. Metzincin proteases and their inhibitors: foes or friends in nervous system physiology? J Neurosci 2010; 30:15337-57. [PMID: 21084591 PMCID: PMC3072038 DOI: 10.1523/jneurosci.3467-10.2010] [Citation(s) in RCA: 184] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Revised: 09/02/2010] [Accepted: 09/20/2010] [Indexed: 12/19/2022] Open
Abstract
Members of the metzincin family of metalloproteinases have long been considered merely degradative enzymes for extracellular matrix molecules. Recently, however, there has been growing appreciation for these proteinases and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), as fine modulators of nervous system physiology and pathology. Present all along the phylogenetic tree, in all neural cell types, from the nucleus to the synapse and in the extracellular space, metalloproteinases exhibit a complex spatiotemporal profile of expression in the nervous parenchyma and at the neurovascular interface. The irreversibility of their proteolytic activity on numerous biofactors (e.g., growth factors, cytokines, receptors, DNA repair enzymes, matrix proteins) is ideally suited to sustain structural changes that are involved in physiological or postlesion remodeling of neural networks, learning consolidation or impairment, neurodegenerative and neuroinflammatory processes, or progression of malignant gliomas. The present review provides a state of the art overview of the involvement of the metzincin/TIMP system in these processes and the prospects of new therapeutic strategies based on the control of metalloproteinase activity.
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Affiliation(s)
- Santiago Rivera
- Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, Unité Mixte de Recherche 6184, Centre National de la Recherche Scientifique, Université de la Méditerranée, 13344 Marseille, France
| | - Michel Khrestchatisky
- Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, Unité Mixte de Recherche 6184, Centre National de la Recherche Scientifique, Université de la Méditerranée, 13344 Marseille, France
| | | | - Gary A. Rosenberg
- Departments of Neurology, Neurosciences, Cell Biology, and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, and
| | - Diane M. Jaworski
- Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, Vermont 05405
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33
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Canault M, Certel K, Schatzberg D, Wagner DD, Hynes RO. The lack of ADAM17 activity during embryonic development causes hemorrhage and impairs vessel formation. PLoS One 2010; 5:e13433. [PMID: 20976179 PMCID: PMC2955552 DOI: 10.1371/journal.pone.0013433] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Accepted: 09/21/2010] [Indexed: 12/20/2022] Open
Abstract
Background ADAM17/TACE activity is important during embryonic development. We wished to investigate possible roles of this metalloprotease, focusing on vascular development. Methodology/Principal Findings Mice mutant in the enzymatic activity of ADAM17 were examined at various stages of embryonic development for vascular pattern and integrity using markers for vessel wall cells. We observed hemorrhage and edema starting at embryonic day E14.5 and becoming more severe as development proceeded; prior to embryonic day E14.5, embryos appeared normal. Staining for PECAM-1/CD31 revealed abnormalities in the patterns of branching of the embryonic vasculature at E14.5. Conclusions/Significance These abnormalities preceded association of pericytes or monocyte/macrophage cells with the affected vessels and, therefore, presumably arise from defects in endothelial function consequent upon failure of ADAM17 to cleave one or more substrates involved in vascular development, such as Notch, Delta, VEGFR2 or JAM-A. Our study demonstrates a role for ADAM17 in modulating embryonic vessel development and function.
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Affiliation(s)
- Matthias Canault
- Immune Disease Institute, Boston, Massachusetts, United States of America
- Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts, United States of America
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kaan Certel
- Howard Hughes Medical Institute, Chevy Chase, Massachusetts, United States of America
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
| | - Daphne Schatzberg
- Immune Disease Institute, Boston, Massachusetts, United States of America
- Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts, United States of America
| | - Denisa D. Wagner
- Immune Disease Institute, Boston, Massachusetts, United States of America
- Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, Massachusetts, United States of America
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (DDW); (ROH)
| | - Richard O. Hynes
- Howard Hughes Medical Institute, Chevy Chase, Massachusetts, United States of America
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
- * E-mail: (DDW); (ROH)
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Tumor Necrosis Factor Inhibitors and Lung Disease: A Paradox of Efficacy and Risk. Semin Arthritis Rheum 2010; 40:147-63. [DOI: 10.1016/j.semarthrit.2009.09.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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35
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Abstract
This review focuses on the role of ADAM-17 in disease. Since its debut as the tumor necrosis factor converting enzyme (TACE), ADAM-17 has been reported to be an indispensible regulator of almost every cellular event from proliferation to migration. The central role of ADAM-17 in cell regulation is rooted in its diverse array of substrates: cytokines, growth factors, and their receptors as well as adhesion molecules are activated or inactivated by their cleavage with ADAM-17. It is therefore not surprising that ADAM-17 is implicated in numerous human diseases including cancer, heart disease, diabetes, rheumatoid arthritis, kidney fibrosis, Alzheimer's disease, and is a promising target for future treatments. The specific role of ADAM-17 in the pathophysiology of these diseases is very complex and depends on the cellular context. To exploit the therapeutic potential of ADAM-17, it is important to understand how its activity is regulated and how specific organs and cells can be targeted to inactivate or activate the enzyme.
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Affiliation(s)
- Monika Gooz
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
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36
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Wu K, Liao M, Liu B, Deng Z. ADAM-17 over-expression in gallbladder carcinoma correlates with poor prognosis of patients. Med Oncol 2010; 28:475-80. [PMID: 20300969 DOI: 10.1007/s12032-010-9481-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 03/02/2010] [Indexed: 12/16/2022]
Abstract
The ADAMs is a multi-functional gene family of membrane proteins possessing a disintegrin and metalloprotease domain. They have potential implications for the metastasis of human tumor cells via cell adhesion and protease activities. However, no studies have yet comprehensively examined the expression of ADAMs in gallbladder carcinoma. The aim of this study was to test the hypothesis that ADAM-17 (otherwise known as tumor necrosis factor-α converting enzyme) is involved in the progression of gallbladder carcinoma. Two hundreds samples of gallbladder carcinoma and sixty non-cancerous gallbladder samples were used to measure the expression of total ADAM-17 by enzyme-linked immunosorbent assay, and the precursor and active forms by western blotting analysis. Expression of ADAM-17 was significantly increased in tumors with high histological grade and pT stage compared with low histological grade and pT stage tumors and was not associated with patients' gender, age, histological type, and resection margin involvement. Patients with high expression of ADAM-17 had a significantly shorter overall survival compared with those with low expression. Significantly, the prognostic impact of ADAM-17 was independent of conventional prognostic factors for gallbladder carcinoma. The current study demonstrated that the over-expression of ADAM-17 in patients with gallbladder carcinoma was linked closely with histological grade, pT stage and prognosis, and thus provides further impetus for exploiting ADAM-17 as new target for the treatment of gallbladder carcinoma.
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Affiliation(s)
- Kai Wu
- The Xiangya Hospital, Central South University, 410011, Changsha, Hunan Province, China
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37
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Liu W, Purevdorj E, Zscheppang K, von Mayersbach D, Behrens J, Brinkhaus MJ, Nielsen HC, Schmiedl A, Dammann CEL. ErbB4 regulates the timely progression of late fetal lung development. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2010; 1803:832-9. [PMID: 20303366 DOI: 10.1016/j.bbamcr.2010.03.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2009] [Revised: 03/02/2010] [Accepted: 03/03/2010] [Indexed: 02/07/2023]
Abstract
The ErbB4 receptor has an important function in fetal lung maturation. Deletion of ErbB4 leads to alveolar hypoplasia and hyperreactive airways similar to the changes in bronchopulmonary dysplasia (BPD). BPD is a chronic pulmonary disorder affecting premature infants as a consequence of lung immaturity, lung damage, and abnormal repair. We hypothesized that proper ErbB4 function is needed for the timely progression of fetal lung development. An ErbB4 transgenic cardiac rescue mouse model was used to study the effect of ErbB4 deletion on fetal lung structure, surfactant protein (SP) expression, and synthesis, and inflammation. Morphometric analyses revealed a delayed structural development with a significant decrease in saccular size at E18 and more pronounced changes at E17, keeping these lungs in the canalicular stage. SP-B mRNA expression was significantly down regulated at E17 with a subsequent decrease in SP-B protein expression at E18. SP-D protein expression was significantly decreased at E18. Surfactant phospholipid synthesis was significantly decreased on both days, and secretion was down regulated at E18. We conclude that pulmonary ErbB4 deletion results in a structural and functional delay in fetal lung development, indicating a crucial regulatory role of ErbB4 in the timely progression of fetal lung development.
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Affiliation(s)
- Washa Liu
- Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111, USA
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38
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Warburton D, El-Hashash A, Carraro G, Tiozzo C, Sala F, Rogers O, De Langhe S, Kemp PJ, Riccardi D, Torday J, Bellusci S, Shi W, Lubkin SR, Jesudason E. Lung organogenesis. Curr Top Dev Biol 2010; 90:73-158. [PMID: 20691848 PMCID: PMC3340128 DOI: 10.1016/s0070-2153(10)90003-3] [Citation(s) in RCA: 303] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Developmental lung biology is a field that has the potential for significant human impact: lung disease at the extremes of age continues to cause major morbidity and mortality worldwide. Understanding how the lung develops holds the promise that investigators can use this knowledge to aid lung repair and regeneration. In the decade since the "molecular embryology" of the lung was first comprehensively reviewed, new challenges have emerged-and it is on these that we focus the current review. Firstly, there is a critical need to understand the progenitor cell biology of the lung in order to exploit the potential of stem cells for the treatment of lung disease. Secondly, the current familiar descriptions of lung morphogenesis governed by growth and transcription factors need to be elaborated upon with the reinclusion and reconsideration of other factors, such as mechanics, in lung growth. Thirdly, efforts to parse the finer detail of lung bud signaling may need to be combined with broader consideration of overarching mechanisms that may be therapeutically easier to target: in this arena, we advance the proposal that looking at the lung in general (and branching in particular) in terms of clocks may yield unexpected benefits.
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Affiliation(s)
- David Warburton
- The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California, USA
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Caescu CI, Jeschke GR, Turk BE. Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. Biochem J 2009; 424:79-88. [PMID: 19715556 PMCID: PMC2774824 DOI: 10.1042/bj20090549] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The metalloproteinases TACE [tumour necrosis factor alpha-converting enzyme; also known as ADAM17 (a disintegrin and metalloproteinase 17)] and ADAM10 are the primary enzymes responsible for catalysing release of membrane-anchored proteins from the cell surface in metazoan organisms. Although the repertoire of protein substrates for these two proteases is partially overlapping, each one appears to target a subset of unique proteins in vivo. The mechanisms by which the two proteases achieve specificity for particular substrates are not completely understood. We have used peptide libraries to define the cleavage site selectivity of TACE and ADAM10. The two proteases have distinct primary sequence requirements at multiple positions surrounding the cleavage site in their substrates, which allowed us to generate peptide substrates that are highly specific for each of these proteases. The major difference between the two protease specificities maps to the P1' position (immediately downstream of the cleavage site) of the substrate. At this position, TACE is selective for smaller aliphatic residues, whereas ADAM10 can accommodate aromatic amino acids. Using mutagenesis we identified three residues in the S1' pockets of these enzymes that dramatically influence specificity for both peptide and protein substrates. Our results suggest that substrate selectivity of TACE and ADAM10 can be at least partly rationalized by specific features of their active sites.
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Affiliation(s)
| | - Grace R. Jeschke
- Department of Pharmacology, Yale University School of Medicine, P.O. Box 208066, 333 Cedar Street, New Haven, CT 06520
| | - Benjamin E. Turk
- Department of Pharmacology, Yale University School of Medicine, P.O. Box 208066, 333 Cedar Street, New Haven, CT 06520
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40
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Autoactivation of human ADAM8: a novel pre-processing step is required for catalytic activity. Biosci Rep 2009; 29:217-28. [PMID: 18811590 DOI: 10.1042/bsr20080145] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Members of the ADAM (a disintegrin and metalloproteinase) family of proteins possess a multidomain architecture which permits functionalities as adhesion molecules, signalling intermediates and proteolytic enzymes. ADAM8 is found on immune cells and is induced by multiple pro-inflammatory stimuli suggesting a role in inflammation. Here we describe an activation mechanism for recombinant human ADAM8 that is independent from classical PC (pro-protein convertase)-mediated activation. N-terminal sequencing revealed that, unlike other ADAMs, ADAM8 undergoes pre-processing at Glu(158), which fractures the Pro (pro-segment)-domain before terminal activation takes place to remove the putative cysteine switch (Cys(167)). ADAM8 lacking the DIS (disintegrin) and/or CR (cysteine-rich) and EGF (epidermal growth factor) domains displayed impaired ability to complete this event. Thus pre-processing of the Pro-domain is co-ordinated by DIS and CR/EGF domains. Furthermore, by placing an EK (enterokinase) recognition motif between the Pro- and catalytic domains of multiple constructs, we were able to artificially remove the pro-segment prior to pre-processing. In the absence of pre-processing of the Pro-domain a marked decrease in specific activity was observed with the autoactivated enzyme, suggesting that the Pro-domain continued to associate and inhibit active enzyme. Thus, pre-processing of the Pro-domain of human ADAM8 is important for enzyme maturation by preventing re-association of the pro-segment with the catalytic domain. Given the observed necessity of DIS and CR/EGF for pre-processing, we conclude that these domains are crucial for the proper activation and maturation of human ADAM8.
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41
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Lucas N, Day ML. The role of the disintegrin metalloproteinase ADAM15 in prostate cancer progression. J Cell Biochem 2009; 106:967-74. [DOI: 10.1002/jcb.22087] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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42
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Göoz P, Göoz M, Baldys A, Hoffman S. ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis. Biochem Biophys Res Commun 2009; 380:33-8. [PMID: 19150341 PMCID: PMC2875258 DOI: 10.1016/j.bbrc.2009.01.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2009] [Accepted: 01/04/2009] [Indexed: 11/21/2022]
Abstract
Modulation of angiogenesis is a promising approach for treating a wide variety of human diseases including ischemic heart disease and cancer. In this study, we show that ADAM-17 is an important regulator of several key steps during angiogenesis. Knocking down ADAM-17 expression using lentivirus-delivered siRNA in HUVECs inhibited cell proliferation and the ability of cells to form close contact in two-dimensional cultures. Similarly, ADAM-17 depletion inhibited the ability of HUVECs to form capillary-like networks on top of three-dimensional Matrigel as well as in co-culture with fibroblasts within a three-dimensional scaffold. In mechanistic studies, both baseline and VEGF-induced MMP-2 activation and Matrigel invasion were inhibited by ADAM-17 depletion. Based on our findings we propose that ADAM-17 is part of a novel pro-angiogenic pathway leading to MMP-2 activation and vessel formation.
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Affiliation(s)
- Pal Göoz
- Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA.
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43
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Dierker T, Dreier R, Petersen A, Bordych C, Grobe K. Heparan sulfate-modulated, metalloprotease-mediated sonic hedgehog release from producing cells. J Biol Chem 2009; 284:8013-22. [PMID: 19176481 DOI: 10.1074/jbc.m806838200] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The ectodomains of numerous proteins are released from cells by matrix metalloproteases to yield soluble intercellular regulators. A disintegrin and metalloprotease (ADAM) family members have often been found to be the responsible "sheddases," ADAM17/tumor necrosis factor-alpha-converting enzyme being its best characterized member. In this work, we show that ShhNp (lipidated and membrane-tethered Sonic hedgehog) is released from Bosc23 cells by metalloprotease-mediated ectodomain shedding, resulting in a soluble and biologically active morphogen. ShhNp shedding is increased by ADAM17 coexpression and cholesterol depletion of cells with methyl-beta-cyclodextrin and is reduced by metalloprotease inhibitors as well as ADAM17 RNA interference. We also show that the amount of shed ShhNp is modulated by extracellular heparan sulfate (HS) and that ShhNp shedding depends on specific HS sulfations. Based on those data, we suggest new roles for metalloproteases, including but not restricted to ADAM17, and for HS-proteoglycans in Hedgehog signaling.
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Affiliation(s)
- Tabea Dierker
- Institute for Physiological Chemistry and Pathobiochemistry, Westfälische Wilhelms-Univertät Münster, Münster, Germany
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44
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Abstract
The epidermal growth factor receptor (EGFR) regulates key processes of cell biology, including proliferation, survival, and differentiation during development, tissue homeostasis, and tumorigenesis. Canonical EGFR activation involves the binding of seven peptide growth factors. These ligands are synthesized as transmembrane proteins comprising an N-terminal extension, the EGF module, a short juxtamembrane stalk, a hydrophobic transmembrane domain, and a carboxy-terminal fragment. The central structural and functional feature is the EGF module, a sequence containing six cysteines in a conserved spacement which is responsible for binding to the EGFR. While the membrane-anchored peptide can be biologically active by juxtacrine signaling, in most cases the EGF module is proteolytically cleaved (a process termed ectodomain shedding) to release the soluble growth factor, which may act in an endocrine, paracrine, or autocrine fashion. This review summarizes the structural and functional properties of these fascinating molecules and presents selected examples to illustrate their roles in development, physiology, and pathology.
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Affiliation(s)
- Marlon R Schneider
- Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany.
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45
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Gelling RW, Yan W, Al-Noori S, Pardini A, Morton GJ, Ogimoto K, Schwartz MW, Dempsey PJ. Deficiency of TNFalpha converting enzyme (TACE/ADAM17) causes a lean, hypermetabolic phenotype in mice. Endocrinology 2008; 149:6053-64. [PMID: 18687778 PMCID: PMC2734496 DOI: 10.1210/en.2008-0775] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Energy homeostasis involves central nervous system integration of afferent inputs that coordinately regulate food intake and energy expenditure. Here, we report that adult homozygous TNFalpha converting enzyme (TACE)-deficient mice exhibit one of the most dramatic examples of hypermetabolism yet reported in a rodent system. Because this effect is not matched by increased food intake, mice lacking TACE exhibit a lean phenotype. In the hypothalamus of these mice, neurons in the arcuate nucleus exhibit intact responses to reduced fat mass and low circulating leptin levels, suggesting that defects in other components of the energy homeostasis system explain the phenotype of Tace(DeltaZn/DeltaZn) mice. Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace(DeltaZn/DeltaZn) mice when compared with weight-matched controls suggest that deficient TACE activity is linked to increased sympathetic outflow. These findings collectively identify a novel and potentially important role for TACE in energy homeostasis.
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Affiliation(s)
- Richard W Gelling
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Washington 98195, USA
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Reiss K, Saftig P. The "a disintegrin and metalloprotease" (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev Biol 2008; 20:126-37. [PMID: 19049889 DOI: 10.1016/j.semcdb.2008.11.002] [Citation(s) in RCA: 312] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Revised: 10/29/2008] [Accepted: 11/06/2008] [Indexed: 01/06/2023]
Abstract
There is an exciting increase of evidence that members of the disintegrin and metalloprotease (ADAM) family critically regulate cell adhesion, migration, development and signalling. ADAMs are involved in "ectodomain shedding" of various cell surface proteins such as growth factors, receptors and their ligands, cytokines, and cell adhesion molecules. The regulation of these proteases is complex and still poorly understood. Studies in ADAM knockout mice revealed their partially redundant roles in angiogenesis, neurogenesis, tissue development and cancer. ADAMs usually trigger the first step in regulated intramembrane proteolysis leading to activation of intracellular signalling pathways and the release of functional soluble ectodomains.
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Affiliation(s)
- Karina Reiss
- Biochemical Institute, Christian-Albrecht-University Kiel, Olshausenstr. 40, D-24098 Kiel, Germany.
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Abstract
The ADAMs (a disintegrin and metalloproteinase) are a fascinating family of transmembrane and secreted proteins with important roles in regulating cell phenotype via their effects on cell adhesion, migration, proteolysis and signalling. Though all ADAMs contain metalloproteinase domains, in humans only 13 of the 21 genes in the family encode functional proteases, indicating that at least for the other eight members, protein-protein interactions are critical aspects of their biological functions. The functional ADAM metalloproteinases are involved in "ectodomain shedding" of diverse growth factors, cytokines, receptors and adhesion molecules. The archetypal activity is shown by ADAM-17 (tumour necrosis factor-alpha convertase, TACE), which is the principal protease involved in the activation of pro-TNF-alpha, but whose sheddase functions cover a broad range of cell surface molecules. In particular, ADAM-17 is required for generation of the active forms of Epidermal Growth Factor Receptor (EGFR) ligands, and its function is essential for the development of epithelial tissues. Several other ADAMs have important sheddase functions in particular tissue contexts. Another major family member, ADAM-10, is a principal player in signalling via the Notch and Eph/ephrin pathways. For a growing number of substrates, foremost among them being Notch, cleavage by ADAM sheddases is essential for their subsequent "regulated intramembrane proteolysis" (RIP), which generates cleaved intracellular domains that translocate to the nucleus and regulate gene transcription. Several ADAMs play roles in spermatogenesis and sperm function, potentially by effecting maturation of sperm and their adhesion and migration in the uterus. Other non-catalytic ADAMs function in the CNS via effects on guidance mechanisms. The ADAM family are thus fundamental to many control processes in development and homeostasis, and unsurprisingly they are also linked to pathological states when their functions are dysregulated, including cancer, cardiovascular disease, asthma, Alzheimer's disease. This review will provide an overview of current knowledge of the human ADAMs, discussing their structure, function, regulation and disease involvement.
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Affiliation(s)
- Dylan R Edwards
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
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Tian L, Wu X, Chi C, Han M, Xu T, Zhuang Y. ADAM10 is essential for proteolytic activation of Notch during thymocyte development. Int Immunol 2008; 20:1181-7. [PMID: 18635581 DOI: 10.1093/intimm/dxn076] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Notch signaling pathway has been shown to play essential roles in T lymphocyte development. Activation of Notch requires a sequential proteolytic cleavage, which converts Notch from the full-length membrane-bound form to a transcriptionally active intracellular fragment. Studies in Drosophila showed that Kuzbanian (Kuz) is responsible for the enzymatic cleavage of extracellular S2 site upon Notch binding to its ligand Delta. Both a disintegrin and metalloprotease (ADAM) 10 and ADAM17, members of the ADAM family metalloproteases, have been indicated as the mammalian counterpart of Kuz in activating Notch in mammals. Here, we investigated functions of ADAM10 in Notch signaling during thymocyte development. We show that conditional disruption of the Adam10 gene in mouse thymocytes results in a developmental defect similar to the phenotypes previously described for T lineage-specific disruption of Notch1. We further show that the activation of Notch1 and its downstream target genes Deltex-1 and Pre-Ta are impaired in Adam10-deficient thymocytes. Our study demonstrates a T cell intrinsic role for Adam10 in activation of Notch1 during thymocyte development.
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Affiliation(s)
- Lei Tian
- Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China
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Minami S, Iwamoto R, Mekada E. HB-EGF decelerates cell proliferation synergistically with TGFalpha in perinatal distal lung development. Dev Dyn 2008; 237:247-58. [PMID: 18069687 DOI: 10.1002/dvdy.21398] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family of growth factors that is suggested to be involved in distal lung development. In HB-EGF null (HB(del/del)) newborns, a histopathologic analysis revealed abnormally thick saccular walls occurring from embryonic day 18.5 that reduced the terminal saccular space area. HB-EGF gene deletion resulted in a significant increase in cell proliferation, indicating that HB-EGF suppresses distal lung cell proliferation. Furthermore, an analysis of saccular morphology and proliferation in HB-EGF and transforming growth factor-alpha (TGFalpha) double-mutant newborns revealed that HB-EGF and TGFalpha function synergistically in this suppression. Finally, crosses between HB(del/del) mice and waved 2 mice, a hypomorphic EGF receptor (EGFR) mutant strain, suggest that HB-EGF and EGFR cooperate in this process. Thus, HB-EGF has a novel suppressive function that contributes to decelerating distal lung cell proliferation synergistically with TGFalpha through EGFR in perinatal distal lung development.
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Affiliation(s)
- Seigo Minami
- Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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50
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Kimura J, Deutsch GH. Key mechanisms of early lung development. Pediatr Dev Pathol 2007; 10:335-47. [PMID: 17929994 DOI: 10.2350/07-06-0290.1] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2007] [Accepted: 07/06/2007] [Indexed: 11/20/2022]
Abstract
Lung morphogenesis requires the integration of multiple regulatory factors, which results in a functional air-blood interface required for gas exchange at birth. The respiratory tract is composed of endodermally derived epithelium surrounded by cells of mesodermal origin. Inductive signaling between these 2 tissue compartments plays a critical role in formation and differentiation of the lung, which is mediated by evolutionarily conserved signaling families used reiteratively during lung formation, including the fibroblast growth factor, hedgehog, retinoic acid, bone morphogenetic protein, and Wnt signaling pathways. Cells coordinate their response to these signaling proteins largely through transcription factors, which determine respiratory cell fate and pattern formation via the activation and repression of downstream target genes. Gain- and loss-of-function studies in null mutant and transgenic mice models have greatly facilitated the identification and hierarchical classification of these molecular programs. In this review, we highlight select molecular events that drive key phases of pulmonary development, including specification of a lung cell fate, primary lung bud formation, tracheoesophageal septation, branching morphogenesis, and proximal-distal epithelial patterning. Understanding the genetic pathways that regulate respiratory tract development is essential to provide insight into the pathogenesis of congenital anomalies and to develop innovative strategies to treat inherited and acquired lung disease.
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Affiliation(s)
- Jun Kimura
- Division of Pathology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
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