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Sun D, Zhao X, Wiegand T, Martin-Lemaitre C, Borianne T, Kleinschmidt L, Grill SW, Hyman AA, Weber C, Honigmann A. Assembly of tight junction belts by ZO1 surface condensation and local actin polymerization. Dev Cell 2025; 60:1234-1250.e6. [PMID: 39742662 DOI: 10.1016/j.devcel.2024.12.012] [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: 03/12/2024] [Revised: 09/30/2024] [Accepted: 12/05/2024] [Indexed: 01/04/2025]
Abstract
Tight junctions play an essential role in sealing tissues, by forming belts of adhesion strands around cellular perimeters. Recent work has shown that the condensation of ZO1 scaffold proteins is required for tight junction assembly. However, the mechanisms by which junctional condensates initiate at cell-cell contacts and elongate around cell perimeters remain unknown. Combining biochemical reconstitutions and live-cell imaging of MDCKII tissue, we found that tight junction belt formation is driven by adhesion receptor-mediated ZO1 surface condensation coupled to local actin polymerization. Adhesion receptor oligomerization provides the signal for surface binding and local condensation of ZO1 at the cell membrane. Condensation produces a molecular scaffold that selectively enriches junctional proteins. Finally, ZO1 condensates directly facilitate local actin polymerization and filament bundling, driving the elongation into a continuous tight junction belt. More broadly, our work identifies how cells couple surface condensation with cytoskeleton organization to assemble and structure adhesion complexes.
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Affiliation(s)
- Daxiao Sun
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Technische Universität Dresden, Biotechnologisches Zentrum, Center for Molecular and Cellular Bioengineering (CMCB), Dresden, Germany.
| | - Xueping Zhao
- Department of Mathematical Sciences, University of Nottingham, Ningbo, China
| | - Tina Wiegand
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Cecilie Martin-Lemaitre
- Technische Universität Dresden, Biotechnologisches Zentrum, Center for Molecular and Cellular Bioengineering (CMCB), Dresden, Germany
| | - Tom Borianne
- Technische Universität Dresden, Biotechnologisches Zentrum, Center for Molecular and Cellular Bioengineering (CMCB), Dresden, Germany
| | - Lennart Kleinschmidt
- Technische Universität Dresden, Biotechnologisches Zentrum, Center for Molecular and Cellular Bioengineering (CMCB), Dresden, Germany
| | - Stephan W Grill
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Cluster of Excellence Physics of Life, TU Dresden, Dresden, Germany
| | - Anthony A Hyman
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Cluster of Excellence Physics of Life, TU Dresden, Dresden, Germany
| | - Christoph Weber
- Faculty of Mathematics, Natural Sciences, and Materials Engineering, Institute of Physics, University of Augsburg, Augsburg, Germany.
| | - Alf Honigmann
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Technische Universität Dresden, Biotechnologisches Zentrum, Center for Molecular and Cellular Bioengineering (CMCB), Dresden, Germany; Cluster of Excellence Physics of Life, TU Dresden, Dresden, Germany.
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Wang D, Mao L, Li K, Wang L, Wang Y, Yang L. sJAM-C as a Potential Biomarker for Coronary Artery Stenosis: Insights from a Clinical Study in Coronary Heart Disease Patients. Diabetes Metab Syndr Obes 2024; 17:4857-4865. [PMID: 39726644 PMCID: PMC11669540 DOI: 10.2147/dmso.s478526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 11/23/2024] [Indexed: 12/28/2024] Open
Abstract
Purpose Coronary artery stenosis caused by atherogenesis is a major pathological link in coronary heart disease (CHD), which is a leading cause of global morbidity and mortality. Junctional adhesion molecule C (JAM-C) presents more and more association with atherosclerosis. However, no studies have shown the relationship between soluble JAM-C (sJAM-C) and the degree of coronary artery stenosis. This study aimed to analyze the effect of sJAM-C on coronary artery stenosis and to verify whether sJAM-C could be a biomarker for coronary artery stenosis. Patients and Methods The participants registered at the Beijing Luhe Hospital, Capital Medical University in the cross-sectional study. A total of 121 patients without coronary stenosis and 408 patients with coronary artery stenosis were enrolled after matching age and sex. Demographic information, medication history, and laboratory data were collected. The level of serum sJAM-C was detected by enzyme-linked immunosorbent assay (ELISA) kits. We used the logistic regression model to evaluate the association between sJAM-C and coronary artery stenosis. Furthermore, the receiver operating characteristic (ROC) curve and area under curve (AUC) were used to evaluate the diagnostic value of sJAM-C on coronary artery stenosis. Results The serum level of sJAM-C was remarkably higher in patients with coronary artery stenosis than those without stenosis (p < 0.0001). Logistic regression models showed that there were positive association between serum sJAM-C level and coronary artery stenosis after adjustment, with corresponding ORs were 3.088 (95% CI 1.922-4.960, p < 0.0001). And the ROC curve revealed a sensitivity of 65.7% and specificity of 60.3% with AUC of 0.676 (95% CI 0.622-0.730) for the diagnosis of coronary artery stenosis with serum sJAM-C at a cut-off value of 18.1 pg/mL, indicating a certain diagnostic value. Conclusion In summary, higher serum sJAM-C level was possibly associated with the more severe coronary artery stenosis. Additionally, sJAM-C demonstrates a certain diagnostic value of coronary artery stenosis. These findings suggest sJAM-C may be a biomarker for coronary artery stenosis.
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Affiliation(s)
- Di Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Lin Mao
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Kun Li
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Lu Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Yan Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
| | - Longyan Yang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing, People’s Republic of China
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Ren T, Zheng Y, Liu F, Liu C, Zhang B, Ren H, Gao X, Wei Y, Sun Q, Huang H. Identification and Validation of JAM-A as a Novel Prognostic and Immune Factor in Human Tumors. Biomedicines 2024; 12:1423. [PMID: 39061997 PMCID: PMC11275048 DOI: 10.3390/biomedicines12071423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/14/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
Junctional adhesion molecule-A (JAM-A), also known as F11 receptor (F11R), is a transmembrane glycoprotein that is involved in various biological processes, including cancer initiation and progression. However, the functional characteristics and significance of JAM-A in pan-cancer remain unexplored. In this study, we used multiple databases to gain a comprehensive understanding of JAM-A in human cancers. JAM-A was widely expressed in various tissues, mainly located on the microtubules and cell junctions. Aberrant expression of JAM-A was detected in multiple cancers at both mRNA and protein levels, which can be correlated with poorer prognosis and may be attributed to genetic alterations and down-regulated DNA methylation. JAM-A expression was also associated with immune infiltration and may affect immunotherapy responses in several cancers. Functional enrichment analysis indicated that JAM-A participated in tight junction and cancer-related pathways. In vitro experiments verified that JAM-A knockdown suppressed the proliferation and migration abilities of breast cancer cells and liver cancer cells. Overall, our study suggests that JAM-A is a pan-cancer regulator and a potential biomarker for predicting prognosis and immune-therapeutic responses for different tumors.
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Affiliation(s)
- Tianyi Ren
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China; (T.R.); (C.L.); (H.R.)
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - You Zheng
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - Feichang Liu
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Chenyu Liu
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China; (T.R.); (C.L.); (H.R.)
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - Bo Zhang
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - He Ren
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China; (T.R.); (C.L.); (H.R.)
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - Xinyue Gao
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - Yuexian Wei
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
- College of Life Science and Bioengineering, School of Science, Beijing Jiaotong University, Beijing 100044, China
| | - Qiang Sun
- Frontier Biotechnology Laboratory, Beijing Institute of Biotechnology, Beijing 100071, China; (Y.Z.); (F.L.); (B.Z.); (X.G.); (Y.W.)
| | - Hongyan Huang
- Department of Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China; (T.R.); (C.L.); (H.R.)
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Hallada LP, Shirinifard A, Solecki DJ. Junctional Adhesion Molecule (JAM)-C recruitment of Pard3 and drebrin to cell contacts initiates neuron-glia recognition and layer-specific cell sorting in developing cerebella. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.26.586832. [PMID: 38585827 PMCID: PMC10996703 DOI: 10.1101/2024.03.26.586832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Sorting maturing neurons into distinct layers is critical for brain development, with disruptions leading to neurological disorders and pediatric cancers. Lamination coordinates where, when, and how cells interact, facilitating events that direct migrating neurons to their destined positions within emerging neural networks and control the wiring of connections in functional circuits. While the role of adhesion molecule expression and presentation in driving adhesive recognition during neuronal migration along glial fibers is recognized, the mechanisms by which the spatial arrangement of these molecules on the cell surface dictates adhesive specificity and translates contact-based external cues into intracellular responses like polarization and cytoskeletal organization remain largely unexplored. We used the cerebellar granule neuron (CGN) system to demonstrate that JAM-C receptor cis-binding on the same cell and trans-binding to neighboring cells controls the recruitment of the Pard3 polarity protein and drebrin microtubule-actin crosslinker at CGN to glial adhesion sites, complementing previous studies that showed Pard3 controls JAM-C exocytic surface presentation. Leveraging advanced imaging techniques, specific probes for cell recognition, and analytical methods to dissect adhesion dynamics, our findings reveal: 1) JAM-C cis or trans mutants result in reduced adhesion formation between CGNs and cerebellar glia, 2) these mutants exhibit delayed recruitment of Pard3 at the adhesion sites, and 3) CGNs with JAM-C mutations experience postponed sorting and entry into the cerebellar molecular layer (ML). By developing a conditional system to image adhesion components from two different cells simultaneously, we made it possible to investigate the dynamics of cell recognition on both sides of neuron-glial contacts and the subsequent recruitment of proteins required for CGN migration. This system and an approach that calculates local correlation based on convolution kernels at the cell adhesions site revealed that CGN to CGN JAM recognition preferentially recruits higher levels of Pard3 and drebrin than CGN to glia JAM recognition. The long latency time of CGNs in the inner external germinal layer (EGL) can be attributed to the combined strength of CGN-CGN contacts and the less efficient Pard3 recruitment by CGN-BG contacts, acting as gatekeepers to ML entry. As CGNs eventually transition to glia binding for radial migration, our research demonstrates that establishing permissive JAM-recognition sites on glia via cis and trans interactions of CGN JAM-C serves as a critical temporal checkpoint for sorting at the EGL to ML boundary. This mechanism integrates intrinsic and extrinsic cellular signals, facilitating heterotypic cell sorting into the ML and dictating the precise spatial organization within the cerebellar architecture.
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Cong X, Mao XD, Wu LL, Yu GY. The role and mechanism of tight junctions in the regulation of salivary gland secretion. Oral Dis 2024; 30:3-22. [PMID: 36825434 DOI: 10.1111/odi.14549] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/27/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023]
Abstract
Tight junctions (TJs) are cell-cell interactions that localize at the most apical portion of epithelial/endothelial cells. One of the predominant functions of TJs is to regulate material transport through paracellular pathway, which serves as a selective barrier. In recent years, the expression and function of TJs in salivary glands has attracted great interest. The characteristics of multiple salivary gland TJ proteins have been identified. During salivation, the activation of muscarinic acetylcholine receptor and transient receptor potential vanilloid subtype 1, as well as other stimuli, promote the opening of acinar TJs by inducing internalization of TJs, thereby contributing to increased paracellular permeability. Besides, endothelial TJs are also redistributed with leakage of blood vessels in cholinergic-stimulated submandibular glands. Furthermore, under pathological conditions, such as Sjögren's syndrome, diabetes mellitus, immunoglobulin G4-related sialadenitis, and autotransplantation, the integrity and barrier function of TJ complex are impaired and may contribute to hyposalivation. Moreover, in submandibular glands of Sjögren's syndrome mouse model and patients, the endothelial barrier is disrupted and involved in hyposecretion and lymphocytic infiltration. These findings enrich our understanding of the secretory mechanisms that link the importance of epithelial and endothelial TJ functions to salivation under both physiological and pathophysiological conditions.
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Affiliation(s)
- Xin Cong
- Center for Salivary Gland Diseases, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Department of Physiology and Pathophysiology, Peking University School of Basic Sciences, Beijing, China
| | - Xiang-Di Mao
- Center for Salivary Gland Diseases, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Department of Physiology and Pathophysiology, Peking University School of Basic Sciences, Beijing, China
| | - Li-Ling Wu
- Center for Salivary Gland Diseases, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
- Department of Physiology and Pathophysiology, Peking University School of Basic Sciences, Beijing, China
| | - Guang-Yan Yu
- Center for Salivary Gland Diseases, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China
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Kamakura S, Hayase J, Kohda A, Iwakiri Y, Chishiki K, Izaki T, Sumimoto H. TMEM25 is a Par3-binding protein that attenuates claudin assembly during tight junction development. EMBO Rep 2024; 25:144-167. [PMID: 38177906 PMCID: PMC10897455 DOI: 10.1038/s44319-023-00018-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 01/06/2024] Open
Abstract
The tight junction (TJ) in epithelial cells is formed by integral membrane proteins and cytoplasmic scaffolding proteins. The former contains the claudin family proteins with four transmembrane segments, while the latter includes Par3, a PDZ domain-containing adaptor that organizes TJ formation. Here we show the single membrane-spanning protein TMEM25 localizes to TJs in epithelial cells and binds to Par3 via a PDZ-mediated interaction with its C-terminal cytoplasmic tail. TJ development during epithelial cell polarization is accelerated by depletion of TMEM25, and delayed by overexpression of TMEM25 but not by that of a C-terminally deleted protein, indicating a regulatory role of TMEM25. TMEM25 associates via its N-terminal extracellular domain with claudin-1 and claudin-2 to suppress their cis- and trans-oligomerizations, both of which participate in TJ strand formation. Furthermore, Par3 attenuates TMEM25-claudin association via binding to TMEM25, implying its ability to affect claudin oligomerization. Thus, the TJ protein TMEM25 appears to negatively regulate claudin assembly in TJ formation, which regulation is modulated by its interaction with Par3.
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Affiliation(s)
- Sachiko Kamakura
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Junya Hayase
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Akira Kohda
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yuko Iwakiri
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kanako Chishiki
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Tomoko Izaki
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hideki Sumimoto
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
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Godbole NM, Chowdhury AA, Chataut N, Awasthi S. Tight Junctions, the Epithelial Barrier, and Toll-like Receptor-4 During Lung Injury. Inflammation 2022; 45:2142-2162. [PMID: 35779195 PMCID: PMC9649847 DOI: 10.1007/s10753-022-01708-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/31/2022] [Accepted: 06/13/2022] [Indexed: 11/25/2022]
Abstract
Lung epithelium is constantly exposed to the environment and is critically important for the orchestration of initial responses to infectious organisms, toxins, and allergic stimuli, and maintenance of normal gaseous exchange and pulmonary function. The integrity of lung epithelium, fluid balance, and transport of molecules is dictated by the tight junctions (TJs). The TJs are formed between adjacent cells. We have focused on the topic of the TJ structure and function in lung epithelial cells. This review includes a summary of the last twenty years of literature reports published on the disrupted TJs and epithelial barrier in various lung conditions and expression and regulation of specific TJ proteins against pathogenic stimuli. We discuss the molecular signaling and crosstalk among signaling pathways that control the TJ structure and function. The Toll-like receptor-4 (TLR4) recognizes the pathogen- and damage-associated molecular patterns released during lung injury and inflammation and coordinates cellular responses. The molecular aspects of TLR4 signaling in the context of TJs or the epithelial barrier are not fully known. We describe the current knowledge and possible networking of the TLR4-signaling with cellular and molecular mechanisms of TJs, lung epithelial barrier function, and resistance to treatment strategies.
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Affiliation(s)
- Nachiket M Godbole
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA
| | - Asif Alam Chowdhury
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA
| | - Neha Chataut
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA
| | - Shanjana Awasthi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, 1110 N. Stonewall Avenue, Oklahoma City, OK, 73117, USA.
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Boni N, Shapiro L, Honig B, Wu Y, Rubinstein R. On the formation of ordered protein assemblies in cell-cell interfaces. Proc Natl Acad Sci U S A 2022; 119:e2206175119. [PMID: 35969779 PMCID: PMC9407605 DOI: 10.1073/pnas.2206175119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/20/2022] [Indexed: 11/18/2022] Open
Abstract
Crystal structures of many cell-cell adhesion receptors reveal the formation of linear "molecular zippers" comprising an ordered one-dimensional array of proteins that form both intercellular (trans) and intracellular (cis) interactions. The clustered protocadherins (cPcdhs) provide an exemplar of this phenomenon and use it as a basis of barcoding of vertebrate neurons. Here, we report both Metropolis and kinetic Monte Carlo simulations of cPcdh zipper formation using simplified models of cPcdhs that nevertheless capture essential features of their three-dimensional structure. The simulations reveal that the formation of long zippers is an implicit feature of cPcdh structure and is driven by their cis and trans interactions that have been quantitatively characterized in previous work. Moreover, in agreement with cryo-electron tomography studies, the zippers are found to organize into two-dimensional arrays even in the absence of attractive interactions between individual zippers. Our results suggest that the formation of ordered two-dimensional arrays of linear zippers of adhesion proteins is a common feature of cell-cell interfaces. From the perspective of simulations, they demonstrate the importance of a realistic depiction of adhesion protein structure and interactions if important biological phenomena are to be properly captured.
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Affiliation(s)
- Nadir Boni
- School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Lawrence Shapiro
- Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032
| | - Barry Honig
- Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032
- Department of Systems Biology, Columbia University, New York, NY 10032
- Department of Medicine, Division of Nephrology, Columbia University, New York, NY 10032
| | - Yinghao Wu
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461
| | - Rotem Rubinstein
- School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv-Yafo, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv-Yafo, Israel
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Wang J, Chen X. Junctional Adhesion Molecules: Potential Proteins in Atherosclerosis. Front Cardiovasc Med 2022; 9:888818. [PMID: 35872908 PMCID: PMC9302484 DOI: 10.3389/fcvm.2022.888818] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Junctional adhesion molecules (JAMs) are cell-cell adhesion molecules of the immunoglobulin superfamily and are involved in the regulation of diverse atherosclerosis-related processes such as endothelial barrier maintenance, leucocytes transendothelial migration, and angiogenesis. To combine and further broaden related results, this review concluded the recent progress in the roles of JAMs and predicted future studies of JAMs in the development of atherosclerosis.
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Affiliation(s)
- Junqi Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoping Chen,
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Li M, Huang Q, Lv X, Small HJ, Li C. Integrative omics analysis highlights the immunomodulatory effects of the parasitic dinoflagellate hhematodinium on crustacean hemocytes. FISH & SHELLFISH IMMUNOLOGY 2022; 125:35-47. [PMID: 35526798 DOI: 10.1016/j.fsi.2022.04.050] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/24/2022] [Accepted: 04/29/2022] [Indexed: 06/14/2023]
Abstract
Parasitic dinoflagellates in genus Hematodinium have caused substantial economic losses to multiple commercially valuable marine crustaceans around the world. Recent efforts to better understand the life cycle and biology of the parasite have improved our understanding of the disease ecology. However, studies on the host-parasite interaction, especially how Hematodinium parasites evade the host immune response are lacking. To address this shortfall, we used the comprehensive omics approaches (miRNA transcriptomics, iTRAQ-based proteomics) to get insights into the host-parasite interaction between hemocytes from Portunus trituberculatus and Hematodinium perezi in the present study. The parasitic dinoflagellate H. perezi remodeled the miRNome and proteome of hemocytes from challenged hosts, modulated the host immune response at both post-transcriptional and translational levels and caused post-transcriptional regulation to the host immune response. Multiple important cellular and humoral immune-related pathways (ex. Apoptosis, Endocytosis, ECM-receptor interaction, proPO activation pathway, Toll-like signaling pathway, Jak-STAT signaling pathway) were significantly affected by Hematodinium parasites. Through modulation of the host miRNome, the host immune responses of nodulation, proPO activation and antimicrobial peptides were significantly suppressed. Cellular homeostasis was imbalanced via post-transcriptional dysregulation of the phagosome and peroxisome pathways. Cellular structure and communication was seriously impacted by post-transcriptional downregulation of ECM-receptor interaction and focal adhesion pathways. In conclusion, H. perezi parasites could trigger striking changes in the miRNome and proteome of crustacean hemocytes, and this parasite exhibited multifaceted immunomodulatory effects and potential immune-suppressive mechanisms in crustacean hosts.
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Affiliation(s)
- Meng Li
- CAS Key Lab of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Marine Ecology and Environmental Science Laboratory, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China; Centre for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Qian Huang
- CAS Key Lab of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiaoyang Lv
- CAS Key Lab of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hamish J Small
- Virginia Institute of Marine Science, William & Mary, P.O. Box 1346, Gloucester Point, VA, 23062, USA.
| | - Caiwen Li
- CAS Key Lab of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Marine Ecology and Environmental Science Laboratory, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China; Centre for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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Fan S, Smith MS, Keeney J, O’Leary MN, Nusrat A, Parkos CA. JAM-A signals through the Hippo pathway to regulate intestinal epithelial proliferation. iScience 2022; 25:104316. [PMID: 35602956 PMCID: PMC9114518 DOI: 10.1016/j.isci.2022.104316] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 03/18/2022] [Accepted: 04/22/2022] [Indexed: 01/25/2023] Open
Abstract
JAM-A is a tight-junction-associated protein that contributes to regulation of intestinal homeostasis. We report that JAM-A interacts with NF2 and LATS1, functioning as an initiator of the Hippo signaling pathway, well-known for regulation of proliferation. Consistent with these findings, we observed increased YAP activity in JAM-A-deficient intestinal epithelial cells (IEC). Furthermore, overexpression of a dimerization-deficient mutant, JAM-A-DL1, failed to initiate Hippo signaling, phenocopying JAM-A-deficient IEC, whereas overexpression of JAM-A-WT activated Hippo signaling and suppressed proliferation. Lastly, we identify EVI1, a transcription factor reported to promote cellular proliferation, as a contributor to the pro-proliferative phenotype in JAM-A-DL1 overexpressing IEC downstream of YAP. Collectively, our findings establish a new role for JAM-A as a cell-cell contact sensor, raising implications for understanding the contribution(s) of JAM-A to IEC proliferation in the mammalian epithelium.
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Affiliation(s)
- Shuling Fan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Michelle Sydney Smith
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Justin Keeney
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Monique N. O’Leary
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Asma Nusrat
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Charles A. Parkos
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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12
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Smith YE, Wang G, Flynn CL, Madden SF, MacEneaney O, Cruz RGB, Richards CE, Jahns H, Brennan M, Cremona M, Hennessy BT, Sheehan K, Casucci A, Sani FA, Hudson L, Fay J, Vellanki SH, O’Flaherty S, Devocelle M, Hill ADK, Brennan K, Sukumar S, Hopkins AM. Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression. Cancers (Basel) 2022; 14:cancers14051303. [PMID: 35267611 PMCID: PMC8909510 DOI: 10.3390/cancers14051303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Specific drug targets for breast ductal carcinoma in situ (DCIS) remain elusive, despite increasing disease prevalence and burden to healthcare services. Estrogen receptor (ER)-negative HER2-positive DCIS, associated with the poorest patient prognosis, is in particular need of novel therapeutic avenues. This report provides the first evidence that a cell surface protein called JAM-A is upregulated on human DCIS patient tissues and can be readily targeted by a novel JAM-A-binding peptide inhibitor in separate in vivo models of DCIS. The anti-tumor efficacy and lack of systemic toxicity of this lead inhibitor, coupled with early indications of potential signaling pathways implicated, support the value of future studies investigating JAM-A as a novel drug target in DCIS patients. Abstract Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS.
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Affiliation(s)
- Yvonne E. Smith
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Guannan Wang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (G.W.); (S.S.)
| | - Ciara L. Flynn
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Stephen F. Madden
- Data Science Centre, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland;
| | - Owen MacEneaney
- Department of Pathology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (O.M.); (K.S.); (J.F.)
| | - Rodrigo G. B. Cruz
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Cathy E. Richards
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Hanne Jahns
- School of Veterinary Medicine, University College Dublin, Dublin 4, Ireland;
| | - Marian Brennan
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland;
| | - Mattia Cremona
- Department of Medical Oncology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (M.C.); (B.T.H.)
| | - Bryan T. Hennessy
- Department of Medical Oncology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (M.C.); (B.T.H.)
| | - Katherine Sheehan
- Department of Pathology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (O.M.); (K.S.); (J.F.)
| | - Alexander Casucci
- School of Medicine, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland; (A.C.); (F.A.S.)
| | - Faizah A. Sani
- School of Medicine, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland; (A.C.); (F.A.S.)
| | - Lance Hudson
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Joanna Fay
- Department of Pathology, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (O.M.); (K.S.); (J.F.)
| | - Sri H. Vellanki
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Siobhan O’Flaherty
- Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland; (S.O.); (M.D.)
| | - Marc Devocelle
- Department of Chemistry, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland; (S.O.); (M.D.)
| | - Arnold D. K. Hill
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Kieran Brennan
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
| | - Saraswati Sukumar
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; (G.W.); (S.S.)
| | - Ann M. Hopkins
- Department of Surgery, RCSI University of Medicine and Health Sciences, Beaumont Hospital, Dublin 9, Ireland; (Y.E.S.); (C.L.F.); (R.G.B.C.); (C.E.R.); (L.H.); (S.H.V.); (A.D.K.H.); (K.B.)
- Correspondence: ; Tel.: +353-1-809-3858
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13
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To Stick or Not to Stick: Adhesions in Orofacial Clefts. BIOLOGY 2022; 11:biology11020153. [PMID: 35205020 PMCID: PMC8869391 DOI: 10.3390/biology11020153] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 11/17/2022]
Abstract
Morphogenesis requires a tight coordination between mechanical forces and biochemical signals to inform individual cellular behavior. For these developmental processes to happen correctly the organism requires precise spatial and temporal coordination of the adhesion, migration, growth, differentiation, and apoptosis of cells originating from the three key embryonic layers, namely the ectoderm, mesoderm, and endoderm. The cytoskeleton and its remodeling are essential to organize and amplify many of the signaling pathways required for proper morphogenesis. In particular, the interaction of the cell junctions with the cytoskeleton functions to amplify the behavior of individual cells into collective events that are critical for development. In this review we summarize the key morphogenic events that occur during the formation of the face and the palate, as well as the protein complexes required for cell-to-cell adhesions. We then integrate the current knowledge into a comprehensive review of how mutations in cell-to-cell adhesion genes lead to abnormal craniofacial development, with a particular focus on cleft lip with or without cleft palate.
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14
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Mendoza C, Nagidi SH, Collett K, Mckell J, Mizrachi D. Calcium regulates the interplay between the tight junction and epithelial adherens junction at the plasma membrane. FEBS Lett 2022; 596:219-231. [PMID: 34882783 DOI: 10.1002/1873-3468.14252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/05/2021] [Accepted: 12/05/2021] [Indexed: 01/15/2023]
Abstract
The apical junctional complex (AJC) is a membrane protein ultrastructure that regulates cell adhesion and homeostasis. The tight junction (TJ) and the adherens junction (AJ) are substructures of the AJC. The interplay between TJ and AJ membrane proteins to assemble the AJC remains unclear. We employed synthetic biology strategies to express the basic membrane elements of a simple AJC-the adhesive extracellular domains of junctional adhesion molecule A (JAM-A), epithelial cadherin, claudin 1, and occludin-to study their interactions. Our results suggest that calcium concentration fluctuations and JAM-A, acting as an interface molecule between the TJ and AJ, orchestrate their interplay. Calcium affects the secondary structure, oligomerization, and binding affinity of homotypic and heterotypic interactions of TJ and AJ components, thus acting as a molecular switch influencing AJC dynamics.
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Affiliation(s)
- Christopher Mendoza
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Sai Harsha Nagidi
- Department of Molecular Microbiology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Kjetil Collett
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Jacob Mckell
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Dario Mizrachi
- Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
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15
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Czubak-Prowizor K, Babinska A, Swiatkowska M. The F11 Receptor (F11R)/Junctional Adhesion Molecule-A (JAM-A) (F11R/JAM-A) in cancer progression. Mol Cell Biochem 2021; 477:79-98. [PMID: 34533648 PMCID: PMC8755661 DOI: 10.1007/s11010-021-04259-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 09/08/2021] [Indexed: 12/27/2022]
Abstract
The F11 Receptor (F11R), also called Junctional Adhesion Molecule-A (JAM-A) (F11R/JAM-A), is a transmembrane glycoprotein of the immunoglobulin superfamily, which is mainly located in epithelial and endothelial cell tight junctions and also expressed on circulating platelets and leukocytes. It participates in the regulation of various biological processes, as diverse as paracellular permeability, tight junction formation and maintenance, leukocyte transendothelial migration, epithelial-to-mesenchymal transition, angiogenesis, reovirus binding, and platelet activation. Dysregulation of F11R/JAM-A may result in pathological consequences and disorders in normal cell function. A growing body of evidence points to its role in carcinogenesis and invasiveness, but its tissue-specific pro- or anti-tumorigenic role remains a debated issue. The following review focuses on the F11R/JAM-A tissue-dependent manner in tumorigenesis and metastasis and also discusses the correlation between poor patient clinical outcomes and its aberrant expression. In the future, it will be required to clarify the signaling pathways that are activated or suppressed via the F11R/JAM-A protein in various cancer types to understand its multiple roles in cancer progression and further use it as a novel direct target for cancer treatment.
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Affiliation(s)
- Kamila Czubak-Prowizor
- Department of Cytobiology and Proteomics, Medical University of Lodz, 6/8 Mazowiecka St., 92-215, Lodz, Poland.
| | - Anna Babinska
- Department of Medicine, State University of New York Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY, 11203, USA
| | - Maria Swiatkowska
- Department of Cytobiology and Proteomics, Medical University of Lodz, 6/8 Mazowiecka St., 92-215, Lodz, Poland
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16
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Eom DS, Patterson LB, Bostic RR, Parichy DM. Immunoglobulin superfamily receptor Junctional adhesion molecule 3 (Jam3) requirement for melanophore survival and patterning during formation of zebrafish stripes. Dev Biol 2021; 476:314-327. [PMID: 33933422 PMCID: PMC10069301 DOI: 10.1016/j.ydbio.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/03/2021] [Accepted: 04/22/2021] [Indexed: 12/14/2022]
Abstract
Adhesive interactions are essential for tissue patterning and morphogenesis yet difficult to study owing to functional redundancies across genes and gene families. A useful system in which to dissect roles for cell adhesion and adhesion-dependent signaling is the pattern formed by pigment cells in skin of adult zebrafish, in which stripes represent the arrangement of neural crest derived melanophores, cells homologous to melanocytes. In a forward genetic screen for adult pattern defects, we isolated the pissarro (psr) mutant, having a variegated phenotype of spots, as well as defects in adult fin and lens. We show that psr corresponds to junctional adhesion protein 3b (jam3b) encoding a zebrafish orthologue of the two immunoglobulin-like domain receptor JAM3 (JAM-C), known for roles in adhesion and signaling in other developing tissues, and for promoting metastatic behavior of human and murine melanoma cells. We found that zebrafish jam3b is expressed post-embryonically in a variety of cells including melanophores, and that jam3b mutants have defects in melanophore survival. Jam3b supported aggregation of cells in vitro and was required autonomously by melanophores for an adherent phenotype in vivo. Genetic analyses further indicated both overlapping and non-overlapping functions with the related receptor, Immunoglobulin superfamily 11 (Igsf11) and Kit receptor tyrosine kinase. These findings suggest a model for Jam3b function in zebrafish melanophores and hint at the complexity of adhesive interactions underlying pattern formation.
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Affiliation(s)
- Dae Seok Eom
- Department of Biology, University of Virginia, Charlottesville, VA, USA.
| | | | - Raegan R Bostic
- Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA
| | - David M Parichy
- Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
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17
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Unique C-terminal extension and interactome of Mycobacterium tuberculosis GlmU impacts it's in vivo function and the survival of pathogen. Biochem J 2021; 478:2081-2099. [PMID: 33955473 DOI: 10.1042/bcj20210170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/01/2021] [Accepted: 05/06/2021] [Indexed: 11/17/2022]
Abstract
N-acetyl glucosamine-1-phosphate uridyltransferase (GlmU) is a bifunctional enzyme involved in the biosynthesis of Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is a critical precursor for the synthesis of peptidoglycan and other cell wall components. The absence of a homolog in eukaryotes makes GlmU an attractive target for therapeutic intervention. Mycobacterium tuberculosis GlmU (GlmUMt) has features, such as a C-terminal extension, that are not present in GlmUorthologs from other bacteria. Here, we set out to determine the uniqueness of GlmUMt by performing in vivo complementation experiments using RvΔglmU mutant. We find that any deletion of the carboxy-terminal extension region of GlmUMt abolishes its ability to complement the function of GlmUMt. Results show orthologs of GlmU, including its closest ortholog, from Mycobacterium smegmatis, cannot complement the function of GlmUMt. Furthermore, the co-expression of GlmUMt domain deletion mutants with either acetyl or uridyltransferase activities failed to rescue the function. However, co-expression of GlmUMt point mutants with either acetyl or uridyltransferase activities successfully restored the biological function of GlmUMt, likely due to the formation of heterotrimers. Based on the interactome experiments, we speculate that GlmUMt participates in unique interactions essential for its in vivo function.
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18
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Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review. Pharmaceutics 2020; 12:pharmaceutics12121236. [PMID: 33352631 PMCID: PMC7767277 DOI: 10.3390/pharmaceutics12121236] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/19/2022] Open
Abstract
The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and express specific polarized transport systems to tightly control the paracellular movements of solutes, ions, and water. There are two types of TJs: bicellular TJs (bTJs), which is a structure at the contact of two cells, and tricellular TJs (tTJs), which is a structure at the contact of three cells. Claudin-5 and angulin-1 are important components of bTJs and tTJs in the brain, respectively. Here, we review TJ-modulating bioprobes that enable drug delivery to the brain across the BBB, focusing on claudin-5 and angulin-1.
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19
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Bonilha CS, Benson RA, Brewer JM, Garside P. Targeting Opposing Immunological Roles of the Junctional Adhesion Molecule-A in Autoimmunity and Cancer. Front Immunol 2020; 11:602094. [PMID: 33324419 PMCID: PMC7723963 DOI: 10.3389/fimmu.2020.602094] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/02/2020] [Indexed: 01/04/2023] Open
Abstract
The junctional adhesion molecule-A (JAM-A) is a cell surface adhesion molecule expressed on platelets, epithelial cells, endothelial cells and leukocytes (e. g. monocytes and dendritic cells). JAM-A plays a relevant role in leukocyte trafficking and its therapeutic potential has been studied in several pathological conditions due to its capacity to induce leukocyte migration out of inflamed sites or infiltration into tumor sites. However, disruption of JAM-A pathways may worsen clinical pathology in some cases. As such, the effects of JAM-A manipulation on modulating immune responses in the context of different diseases must be better understood. In this mini-review, we discuss the potential of JAM-A as a therapeutic target, summarizing findings from studies manipulating JAM-A in the context of inflammatory diseases (e.g. autoimmune diseases) and cancer and highlighting described mechanisms.
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Affiliation(s)
- Caio S. Bonilha
- College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Robert A. Benson
- College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
- Research and Development Department, Antibody Analytics Ltd., Newhouse, Lanarkshire, United Kingdom
| | - James M. Brewer
- College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Paul Garside
- College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
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20
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Rathjen FG. The CAR group of Ig cell adhesion proteins–Regulators of gap junctions? Bioessays 2020; 42:e2000031. [DOI: 10.1002/bies.202000031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 09/01/2020] [Indexed: 12/29/2022]
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21
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Díaz-Díaz C, Baonza G, Martín-Belmonte F. The vertebrate epithelial apical junctional complex: Dynamic interplay between Rho GTPase activity and cell polarization processes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183398. [DOI: 10.1016/j.bbamem.2020.183398] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/05/2020] [Accepted: 06/11/2020] [Indexed: 12/31/2022]
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Special Issue on "The Tight Junction and Its Proteins: More than Just a Barrier". Int J Mol Sci 2020; 21:ijms21134612. [PMID: 32610530 PMCID: PMC7370070 DOI: 10.3390/ijms21134612] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
For a long time, the tight junction (TJ) was known to form and regulate the paracellular barrier between epithelia and endothelial cell sheets. Starting shortly after the discovery of the proteins forming the TJ—mainly, the two families of claudins and TAMPs—several other functions have been discovered, a striking one being the surprising finding that some claudins form paracellular channels for small ions and/or water. This Special Issue covers numerous dedicated topics including pathogens affecting the TJ barrier, TJ regulation via immune cells, the TJ as a therapeutic target, TJ and cell polarity, the function of and regulation by proteins of the tricellular TJ, the TJ as a regulator of cellular processes, organ- and tissue-specific functions, TJs as sensors and reactors to environmental conditions, and last, but not least, TJ proteins and cancer. It is not surprising that due to this diversity of topics and functions, the still-young field of TJ research is growing fast. This Editorial gives an introduction to all 43 papers of the Special Issue in a structured topical order.
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Heinemann U, Schuetz A. Structural Features of Tight-Junction Proteins. Int J Mol Sci 2019; 20:E6020. [PMID: 31795346 PMCID: PMC6928914 DOI: 10.3390/ijms20236020] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 11/25/2019] [Accepted: 11/26/2019] [Indexed: 12/14/2022] Open
Abstract
Tight junctions are complex supramolecular entities composed of integral membrane proteins, membrane-associated and soluble cytoplasmic proteins engaging in an intricate and dynamic system of protein-protein interactions. Three-dimensional structures of several tight-junction proteins or their isolated domains have been determined by X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy. These structures provide direct insight into molecular interactions that contribute to the formation, integrity, or function of tight junctions. In addition, the known experimental structures have allowed the modeling of ligand-binding events involving tight-junction proteins. Here, we review the published structures of tight-junction proteins. We show that these proteins are composed of a limited set of structural motifs and highlight common types of interactions between tight-junction proteins and their ligands involving these motifs.
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Affiliation(s)
- Udo Heinemann
- Macromolecular Structure and Interaction Laboratory, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
| | - Anja Schuetz
- Protein Production & Characterization Platform, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
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24
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Su Z, Wu Y. Computational simulations of TNF receptor oligomerization on plasma membrane. Proteins 2019; 88:698-709. [PMID: 31710744 DOI: 10.1002/prot.25854] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/30/2019] [Accepted: 11/05/2019] [Indexed: 12/21/2022]
Abstract
The interactions between tumor necrosis factors (TNFs) and their corresponding receptors (TNFRs) play a pivotal role in inflammatory responses. Upon ligand binding, TNFR receptors were found to form oligomers on cell surfaces. However, the underlying mechanism of oligomerization is not fully understood. In order to tackle this problem, molecular dynamics (MD) simulations have been applied to the complex between TNF receptor-1 (TNFR1) and its ligand TNF-α as a specific test system. The simulations on both all-atom (AA) and coarse-grained (CG) levels achieved the similar results that the extracellular domains of TNFR1 can undergo large fluctuations on plasma membrane, while the dynamics of TNFα-TNFR1 complex is much more constrained. Using the CG model with the Martini force field, we are able to simulate the systems that contain multiple TNFα-TNFR1 complexes with the timescale of microseconds. We found that complexes can aggregate into oligomers on the plasma membrane through the lateral interactions between receptors at the end of the CG simulations. We suggest that this spatial organization is essential to the efficiency of signal transduction for ligands that belong to the TNF superfamily. We further show that the aggregation of two complexes is initiated by the association between the N-terminal domains of TNFR1 receptors. Interestingly, the cis-interfaces between N-terminal regions of two TNF receptors have been observed in the previous X-ray crystallographic experiment. Therefore, we provide supportive evidence that cis-interface is of functional importance in triggering the receptor oligomerization. Taken together, our study brings insights to understand the molecular mechanism of TNF signaling.
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Affiliation(s)
- Zhaoqian Su
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Yinghao Wu
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York
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P2X7 Receptor Indirectly Regulates the JAM-A Protein Content via Modulation of GSK-3β. Int J Mol Sci 2019; 20:ijms20092298. [PMID: 31075901 PMCID: PMC6539570 DOI: 10.3390/ijms20092298] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/30/2019] [Accepted: 05/08/2019] [Indexed: 12/20/2022] Open
Abstract
The alveolar epithelial cells represent an important part of the alveolar barrier, which is maintained by tight junction proteins, particularly JAM-A, occludin, and claudin-18, which regulate paracellular permeability. In this study, we report on a strong increase in epithelial JAM-A expression in P2X7 receptor knockout mice when compared to the wildtype. Precision-cut lung slices of wildtype and knockout lungs and immortal epithelial lung E10 cells were treated with bleomycin, the P2X7 receptor inhibitor oxATP, and the agonist BzATP, respectively, to evaluate early changes in JAM-A expression. Biochemical and immunohistochemical data showed evidence for P2X7 receptor-dependent JAM-A expression in vitro. Inhibition of the P2X7 receptor using oxATP increased JAM-A, whereas activation of the receptor decreased the JAM-A protein level. In order to examine the role of GSK-3β in the expression of JAM-A in alveolar epithelial cells, we used lithium chloride for GSK-3β inhibiting experiments, which showed a modulating effect on bleomycin-induced alterations in JAM-A levels. Our data suggest that an increased constitutive JAM-A protein level in P2X7 receptor knockout mice may have a protective effect against bleomycin-induced lung injury. Bleomycin-treated precision-cut lung slices from P2X7 receptor knockout mice responded with a lower increase in mRNA expression of JAM-A than bleomycin-treated precision-cut lung slices from wildtype mice.
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Li M, Wang J, Huang Q, Li C. Proteomic analysis highlights the immune responses of the hepatopancreas against Hematodinium infection in Portunus trituberculatus. J Proteomics 2019; 197:92-105. [DOI: 10.1016/j.jprot.2018.11.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 10/15/2018] [Accepted: 11/16/2018] [Indexed: 12/20/2022]
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Conley MJ, McElwee M, Azmi L, Gabrielsen M, Byron O, Goodfellow IG, Bhella D. Calicivirus VP2 forms a portal-like assembly following receptor engagement. Nature 2019; 565:377-381. [PMID: 30626974 DOI: 10.1038/s41586-018-0852-1] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 12/10/2018] [Indexed: 11/08/2022]
Abstract
To initiate infection, many viruses enter their host cells by triggering endocytosis following receptor engagement. However, the mechanisms by which non-enveloped viruses escape the endosome are poorly understood. Here we present near-atomic-resolution cryo-electron microscopy structures for feline calicivirus both undecorated and labelled with a soluble fragment of its cellular receptor, feline junctional adhesion molecule A. We show that VP2, a minor capsid protein encoded by all caliciviruses1,2, forms a large portal-like assembly at a unique three-fold axis of symmetry, following receptor engagement. This assembly-which was not detected in undecorated virions-is formed of twelve copies of VP2, arranged with their hydrophobic N termini pointing away from the virion surface. Local rearrangement at the portal site leads to the opening of a pore in the capsid shell. We hypothesize that the portal-like assembly functions as a channel for the delivery of the calicivirus genome, through the endosomal membrane, into the cytoplasm of a host cell, thereby initiating infection. VP2 was previously known to be critical for the production of infectious virus3; our findings provide insights into its structure and function that advance our understanding of the Caliciviridae.
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Affiliation(s)
- Michaela J Conley
- Medical Research Council University of Glasgow Centre for Virus Research, Glasgow, UK
| | - Marion McElwee
- Medical Research Council University of Glasgow Centre for Virus Research, Glasgow, UK
| | - Liyana Azmi
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | | | - Olwyn Byron
- School of Life Sciences, University of Glasgow, Glasgow, UK
| | - Ian G Goodfellow
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - David Bhella
- Medical Research Council University of Glasgow Centre for Virus Research, Glasgow, UK.
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Zhou J, Yang A, Wang Y, Chen F, Zhao Z, Davra V, Suzuki-Inoue K, Ozaki Y, Birge RB, Lu Q, Wu Y. Tyro3, Axl, and Mertk receptors differentially participate in platelet activation and thrombus formation. Cell Commun Signal 2018; 16:98. [PMID: 30541554 PMCID: PMC6291976 DOI: 10.1186/s12964-018-0308-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 11/25/2018] [Indexed: 01/09/2023] Open
Abstract
Background Previously, several studies have shown that Tyro3, Axl, and Mertk (TAM) receptors participate in platelet activation and thrombosis. However, the role of individual receptors is not fully understood. Methods Using single receptor-deficient platelets from TAM knockout mice in the C57BL/6 J strain, we performed a knockout study using single TAM-deficient mice. We treated platelets isolated from TAM knockout mice with the Glycoprotein VI (GPVI) agonists convulxin, poly(PHG), and collagen-related triple-helical peptide (CRP), as well as thrombin for in-vitro experiments. We used a laser-induced cremaster arterial injury model for thrombosis experiments in vivo. Results Deficiency of the tyrosine kinase receptors, Axl or Tyro3, but not Mertk, inhibited aggregation, spreading, JON/A binding, and P-selectin expression of platelets in vitro. In vivo, platelet thrombus formation was significantly decreased in Axl−/− and Tyro3−/− mice, but not in Mertk−/− mice. Upon stimulation with glycoprotein VI (GPVI) agonists, tyrosine phosphorylation of signaling molecules, including spleen tyrosine kinase (Syk) and phospholipase C-γ2 (PLCγ2), was decreased in Axl−/− and Tyro3−/− platelets, but not in Mertk−/− platelets. While platelet aggregation induced by agonists did not differ in the presence or absence of the Gas6 neutralizing antibody, the platelet aggregation was inhibited by anti-Axl or anti-Tyro3 neutralizing antibodies antibody, but not the anti-Mertk antibody. Additionally, the recombinant extracellular domain of Axl or Tyro3, but not that of Mertk, also inhibited platelet aggregation. Conclusions These data suggest that Axl and Tyro3, but not Mertk, have an important role in platelet activation and thrombus formation, and mechanistically may do so by a pathway that regulates inside to outside signaling and heterotypic interactions via the extracellular domains of TAMs. Electronic supplementary material The online version of this article (10.1186/s12964-018-0308-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Junsong Zhou
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China.
| | - Aizhen Yang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Yucan Wang
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Fengwu Chen
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Zhenzhen Zhao
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China
| | - Viralkumar Davra
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University-New Jersey Medical School, Newark, NJ, USA
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Yukio Ozaki
- Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Raymond B Birge
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University-New Jersey Medical School, Newark, NJ, USA
| | - Qingxian Lu
- Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY, 40202, USA
| | - Yi Wu
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China. .,The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA19140, USA.
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Steinbacher T, Kummer D, Ebnet K. Junctional adhesion molecule-A: functional diversity through molecular promiscuity. Cell Mol Life Sci 2018; 75:1393-1409. [PMID: 29238845 PMCID: PMC11105642 DOI: 10.1007/s00018-017-2729-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/04/2017] [Accepted: 12/11/2017] [Indexed: 12/27/2022]
Abstract
Cell adhesion molecules (CAMs) of the immunoglobulin superfamily (IgSF) regulate important processes such as cell proliferation, differentiation and morphogenesis. This activity is primarily due to their ability to initiate intracellular signaling cascades at cell-cell contact sites. Junctional adhesion molecule-A (JAM-A) is an IgSF-CAM with a short cytoplasmic tail that has no catalytic activity. Nevertheless, JAM-A is involved in a variety of biological processes. The functional diversity of JAM-A resides to a large part in a C-terminal PDZ domain binding motif which directly interacts with nine different PDZ domain-containing proteins. The molecular promiscuity of its PDZ domain motif allows JAM-A to recruit protein scaffolds to specific sites of cell-cell adhesion and to assemble signaling complexes at those sites. Here, we review the molecular characteristics of JAM-A, including its dimerization, its interaction with scaffolding proteins, and the phosphorylation of its cytoplasmic domain, and we describe how these characteristics translate into diverse biological activities.
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Affiliation(s)
- Tim Steinbacher
- Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Von-Esmarch-Str. 56, 48149, Münster, Germany
- Cells-In-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Münster, Germany
| | - Daniel Kummer
- Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Von-Esmarch-Str. 56, 48149, Münster, Germany
- Interdisciplinary Clinical Research Center (IZKF), University of Münster, Münster, Germany
| | - Klaus Ebnet
- Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Von-Esmarch-Str. 56, 48149, Münster, Germany.
- Cells-In-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Münster, Germany.
- Interdisciplinary Clinical Research Center (IZKF), University of Münster, Münster, Germany.
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Kummer D, Ebnet K. Junctional Adhesion Molecules (JAMs): The JAM-Integrin Connection. Cells 2018; 7:cells7040025. [PMID: 29587442 PMCID: PMC5946102 DOI: 10.3390/cells7040025] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/21/2018] [Accepted: 03/24/2018] [Indexed: 12/22/2022] Open
Abstract
Junctional adhesion molecules (JAMs) are cell surface adhesion receptors of the immunoglobulin superfamily. JAMs are involved in a variety of biological processes both in the adult organism but also during development. These include processes such as inflammation, angiogenesis, hemostasis, or epithelial barrier formation, but also developmental processes such as hematopoiesis, germ cell development, and development of the nervous system. Several of these functions of JAMs depend on a physical and functional interaction with integrins. The JAM – integrin interactions in trans regulate cell-cell adhesion, their interactions in cis regulate signaling processes originating at the cell surface. The JAM – integrin interaction can regulate the function of the JAM as well as the function of the integrin. Beyond the physical interaction with integrins, JAMs can regulate integrin function through intracellular signaling indicating an additional level of JAM – integrin cross-talk. In this review, we describe the various levels of the functional interplay between JAMs and integrins and the role of this interplay during different physiological processes.
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Affiliation(s)
- Daniel Kummer
- Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
- Interdisciplinary Clinical Research Center (IZKF), University of Münster, D-48149 Münster, Germany.
| | - Klaus Ebnet
- Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
- Interdisciplinary Clinical Research Center (IZKF), University of Münster, D-48149 Münster, Germany.
- Cells-In-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, D-48149 Münster, Germany.
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31
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Garrido-Urbani S, Vonlaufen A, Stalin J, De Grandis M, Ropraz P, Jemelin S, Bardin F, Scheib H, Aurrand-Lions M, Imhof BA. Junctional adhesion molecule C (JAM-C) dimerization aids cancer cell migration and metastasis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:638-649. [PMID: 29378216 DOI: 10.1016/j.bbamcr.2018.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 01/10/2018] [Accepted: 01/15/2018] [Indexed: 01/28/2023]
Abstract
Most cancer deaths result from metastasis, which is the dissemination of cells from a primary tumor to distant organs. Metastasis involves changes to molecules that are essential for tumor cell adhesion to the extracellular matrix and to endothelial cells. Junctional Adhesion Molecule C (JAM-C) localizes at intercellular junctions as homodimers or more affine heterodimers with JAM-B. We previously showed that the homodimerization site (E66) in JAM-C is also involved in JAM-B binding. Here we show that neoexpression of JAM-C in a JAM-C-negative carcinoma cell line induced loss of adhesive property and pro-metastatic capacities. We also identify two critical structural sites (E66 and K68) for JAM-C/JAM-B interaction by directed mutagenesis of JAM-C and studied their implication on tumor cell behavior. JAM-C mutants did not bind to JAM-B or localize correctly to junctions. Moreover, mutated JAM-C proteins increased adhesion and reduced proliferation and migration of lung carcinoma cell lines. Carcinoma cells expressing mutant JAM-C grew slower than with JAM-C WT and were not able to establish metastatic lung nodules in mice. Overall these data demonstrate that the dimerization sites E66-K68 of JAM-C affected cell adhesion, polarization and migration and are essential for tumor cell metastasis.
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Affiliation(s)
- Sarah Garrido-Urbani
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
| | - Alain Vonlaufen
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Jimmy Stalin
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Maria De Grandis
- Centre de Recherche en Cancérologie de Marseille, Inserm, UMR1068, Marseille, France; Institut Paoli-Calmettes, Marseille, France; Aix-Marseille Université, Marseille, France; CNRS, UMR7258, Marseille, France
| | - Patricia Ropraz
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Stéphane Jemelin
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Florence Bardin
- Centre de Recherche en Cancérologie de Marseille, Inserm, UMR1068, Marseille, France; Institut Paoli-Calmettes, Marseille, France; Aix-Marseille Université, Marseille, France; CNRS, UMR7258, Marseille, France
| | - Holger Scheib
- Venom Evolution Lab, School of Biological Sciences, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Michel Aurrand-Lions
- Centre de Recherche en Cancérologie de Marseille, Inserm, UMR1068, Marseille, France; Institut Paoli-Calmettes, Marseille, France; Aix-Marseille Université, Marseille, France; CNRS, UMR7258, Marseille, France
| | - Beat A Imhof
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
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Sutherland DM, Aravamudhan P, Dermody TS. An Orchestra of Reovirus Receptors: Still Searching for the Conductor. Adv Virus Res 2017; 100:223-246. [PMID: 29551138 DOI: 10.1016/bs.aivir.2017.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Viruses are constantly engaged in a molecular arms race with the host, where efficient and tactical use of cellular receptors benefits critical steps in infection. Receptor use dictates initiation, establishment, and spread of viral infection to new tissues and hosts. Mammalian orthoreoviruses (reoviruses) are pervasive pathogens that use multiple receptors to overcome protective host barriers to disseminate from sites of initial infection and cause disease in young mammals. In particular, reovirus invades the central nervous system (CNS) with serotype-dependent tropism and disease. A single viral gene, encoding the attachment protein σ1, segregates with distinct patterns of CNS injury. Despite the identification and characterization of several reovirus receptors, host factors that dictate tropism via interaction with σ1 remain undefined. Here, we summarize the state of the reovirus receptor field and discuss open questions toward understanding how the reovirus attachment protein dictates CNS tropism.
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Affiliation(s)
| | | | - Terence S Dermody
- University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
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Ebnet K. Junctional Adhesion Molecules (JAMs): Cell Adhesion Receptors With Pleiotropic Functions in Cell Physiology and Development. Physiol Rev 2017; 97:1529-1554. [PMID: 28931565 DOI: 10.1152/physrev.00004.2017] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/04/2017] [Accepted: 05/11/2017] [Indexed: 02/06/2023] Open
Abstract
Junctional adhesion molecules (JAM)-A, -B and -C are cell-cell adhesion molecules of the immunoglobulin superfamily which are expressed by a variety of tissues, both during development and in the adult organism. Through their extracellular domains, they interact with other adhesion receptors on opposing cells. Through their cytoplasmic domains, they interact with PDZ domain-containing scaffolding and signaling proteins. In combination, these two properties regulate the assembly of signaling complexes at specific sites of cell-cell adhesion. The multitude of molecular interactions has enabled JAMs to adopt distinct cellular functions such as the regulation of cell-cell contact formation, cell migration, or mitotic spindle orientation. Not surprisingly, JAMs regulate diverse processes such as epithelial and endothelial barrier formation, hemostasis, angiogenesis, hematopoiesis, germ cell development, and the development of the central and peripheral nervous system. This review summarizes the recent progress in the understanding of JAMs, including their characteristic structural features, their molecular interactions, their cellular functions, and their contribution to a multitude of processes during vertebrate development and homeostasis.
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Affiliation(s)
- Klaus Ebnet
- Institute-Associated Research Group "Cell Adhesion and Cell Polarity", Institute of Medical Biochemistry, ZMBE, Cells-In-Motion Cluster of Excellence (EXC1003-CiM), and Interdisciplinary Clinical Research Center (IZKF), University of Münster, Münster, Germany
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Hidmark A, Spanidis I, Fleming TH, Volk N, Eckstein V, Groener JB, Kopf S, Nawroth PP, Oikonomou D. Electrical Muscle Stimulation Induces an Increase of VEGFR2 on Circulating Hematopoietic Stem Cells in Patients With Diabetes. Clin Ther 2017; 39:1132-1144.e2. [DOI: 10.1016/j.clinthera.2017.05.340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 05/05/2017] [Accepted: 05/09/2017] [Indexed: 10/19/2022]
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Chen J, Wu Y. Understanding the Functional Roles of Multiple Extracellular Domains in Cell Adhesion Molecules with a Coarse-Grained Model. J Mol Biol 2017; 429:1081-1095. [PMID: 28237680 PMCID: PMC5989558 DOI: 10.1016/j.jmb.2017.02.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 02/08/2017] [Accepted: 02/13/2017] [Indexed: 01/15/2023]
Abstract
Intercellular contacts in multicellular organisms are maintained by membrane receptors called cell adhesion molecules (CAMs), which are expressed on cell surfaces. One interesting feature of CAMs is that almost all of their extracellular regions contain repeating copies of structural domains. It is not clear why so many extracellular domains need to be evolved through natural selection. We tackled this problem by computational modeling. A generic model of CAMs was constructed based on the domain organization of neuronal CAM, which is engaged in maintaining neuron-neuron adhesion in central nervous system. By placing these models on a cell-cell interface, we developed a Monte-Carlo simulation algorithm that incorporates both molecular factors including conformational changes of CAMs and cellular factor including fluctuations of plasma membranes to approach the physical process of CAM-mediated adhesion. We found that the presence of multiple domains at the extracellular region of a CAM plays a positive role in regulating its trans-interaction with other CAMs from the opposite side of cell surfaces. The trans-interaction can further be facilitated by the intramolecular contacts between different extracellular domains of a CAM. Finally, if more than one CAM is introduced on each side of cell surfaces, the lateral binding (cis-interactions) between these CAMs will positively correlate with their trans-interactions only within a small energetic range, suggesting that cell adhesion is an elaborately designed process in which both trans- and cis-interactions are fine-tuned collectively by natural selection. In short, this study deepens our general understanding of the molecular mechanisms of cell adhesion.
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Affiliation(s)
- Jiawen Chen
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY10461, USA
| | - Yinghao Wu
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY10461, USA.
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Identification of Human Junctional Adhesion Molecule 1 as a Functional Receptor for the Hom-1 Calicivirus on Human Cells. mBio 2017; 8:mBio.00031-17. [PMID: 28196955 PMCID: PMC5312078 DOI: 10.1128/mbio.00031-17] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The Hom-1 vesivirus was reported in 1998 following the inadvertent transmission of the animal calicivirus San Miguel sea lion virus to a human host in a laboratory. We characterized the Hom-1 strain and investigated the mechanism by which human cells could be infected. An expression library of 3,559 human plasma membrane proteins was screened for reactivity with Hom-1 virus-like particles, and a single interacting protein, human junctional adhesion molecule 1 (hJAM1), was identified. Transient expression of hJAM1 conferred susceptibility to Hom-1 infection on nonpermissive Chinese hamster ovary (CHO) cells. Virus infection was markedly inhibited when CHO cells stably expressing hJAM were pretreated with anti-hJAM1 monoclonal antibodies. Cell lines of human origin were tested for growth of Hom-1, and efficient replication was observed in HepG2, HuH7, and SK-CO15 cells. The three cell lines (of hepatic or intestinal origin) were confirmed to express hJAM1 on their surface, and clustered regularly interspaced short palindromic repeats/Cas9-mediated knockout of the hJAM1 gene in each line abolished Hom-1 propagation. Taken together, our data indicate that entry of the Hom-1 vesivirus into these permissive human cell lines is mediated by the plasma membrane protein hJAM1 as a functional receptor.IMPORTANCE Vesiviruses, such as San Miguel sea lion virus and feline calicivirus, are typically associated with infection in animal hosts. Following the accidental infection of a laboratory worker with San Miguel sea lion virus, a related virus was isolated in cell culture and named Hom-1. In this study, we found that Hom-1 could be propagated in a number of human cell lines, making it the first calicivirus to replicate efficiently in cultured human cells. Screening of a library of human cell surface membrane proteins showed that the virus could utilize human junctional adhesion molecule 1 as a receptor to enter cells and initiate replication. The Hom-1 virus presents a new system for the study of calicivirus biology and species specificity.
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Backert S, Schmidt TP, Harrer A, Wessler S. Exploiting the Gastric Epithelial Barrier: Helicobacter pylori's Attack on Tight and Adherens Junctions. Curr Top Microbiol Immunol 2017; 400:195-226. [PMID: 28124155 DOI: 10.1007/978-3-319-50520-6_9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which control the microbiota and protect against intruding pathogens in humans. Alterations in these complexes represent key events in the development and progression of multiple infectious diseases as well as various cancers. The gastric pathogen Helicobacter pylori exerts an amazing set of strategies to manipulate these epithelial cell-to-cell junctions, which are implicated in changing cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses. This chapter focuses on the H. pylori pathogenicity factors VacA, CagA, HtrA and urease, and how they can induce host cell signaling involved in altering cell-to-cell permeability. We propose a stepwise model for how H. pylori targets components of tight and adherens junctions in order to disrupt the gastric epithelial cell layer, giving fresh insights into the pathogenesis of this important bacterium.
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Affiliation(s)
- Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstr. 5, 91058, Erlangen, Germany.
| | - Thomas P Schmidt
- Division of Microbiology, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Str. 11, 5020, Salzburg, Austria
| | - Aileen Harrer
- Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Silja Wessler
- Division of Microbiology, Department of Molecular Biology, Paris-Lodron University of Salzburg, Billroth Str. 11, 5020, Salzburg, Austria.
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Matthäus C, Langhorst H, Schütz L, Jüttner R, Rathjen FG. Cell-cell communication mediated by the CAR subgroup of immunoglobulin cell adhesion molecules in health and disease. Mol Cell Neurosci 2016; 81:32-40. [PMID: 27871939 DOI: 10.1016/j.mcn.2016.11.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/16/2016] [Accepted: 11/17/2016] [Indexed: 12/21/2022] Open
Abstract
The immunoglobulin superfamily represents a diverse set of cell-cell contact proteins and includes well-studied members such as NCAM1, DSCAM, L1 or the contactins which are strongly expressed in the nervous system. In this review we put our focus on the biological function of a less understood subgroup of Ig-like proteins composed of CAR (coxsackievirus and adenovirus receptor), CLMP (CAR-like membrane protein) and BT-IgSF (brain and testis specific immunoglobulin superfamily). The CAR-related proteins are type I transmembrane proteins containing an N-terminal variable (V-type) and a membrane proximal constant (C2-type) Ig domain in their extracellular region which are implicated in homotypic adhesion. They are highly expressed during embryonic development in a variety of tissues including the nervous system whereby in adult stages the protein level of CAR and CLMP decreases, only BT-IgSF expression increases within age. CAR-related proteins are concentrated at specialized cell-cell communication sites such as gap or tight junctions and are present at the plasma membrane in larger protein complexes. Considerable progress has been made on the molecular structure and interactions of CAR while research on CLMP and BT-IgSF is at an early stage. Studies on mouse mutants revealed biological functions of CAR in the heart and for CLMP in the gastrointestinal and urogenital systems. Furthermore, CAR and BT-IgSF appear to regulate synaptic function in the hippocampus.
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Affiliation(s)
- Claudia Matthäus
- Max-Delbrück-Center for Molecular Medicine, Developmental Neurobiology, 13092 Berlin, Germany.
| | - Hanna Langhorst
- Max-Delbrück-Center for Molecular Medicine, Developmental Neurobiology, 13092 Berlin, Germany
| | - Laura Schütz
- Max-Delbrück-Center for Molecular Medicine, Developmental Neurobiology, 13092 Berlin, Germany
| | - René Jüttner
- Max-Delbrück-Center for Molecular Medicine, Developmental Neurobiology, 13092 Berlin, Germany
| | - Fritz G Rathjen
- Max-Delbrück-Center for Molecular Medicine, Developmental Neurobiology, 13092 Berlin, Germany.
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Luissint AC, Parkos CA, Nusrat A. Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. Gastroenterology 2016; 151:616-32. [PMID: 27436072 PMCID: PMC5317033 DOI: 10.1053/j.gastro.2016.07.008] [Citation(s) in RCA: 390] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 06/13/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023]
Abstract
The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte-epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation.
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Affiliation(s)
- Anny-Claude Luissint
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Charles A Parkos
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Asma Nusrat
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
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ZHAO HUISHAN, YU HEFEN, MARTIN TRACEYA, TENG XU, JIANG WENG. The role of JAM-B in cancer and cancer metastasis (Review). Oncol Rep 2016; 36:3-9. [PMID: 27121546 PMCID: PMC4899009 DOI: 10.3892/or.2016.4773] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 12/08/2015] [Indexed: 12/31/2022] Open
Abstract
The junctional adhesion molecule B (JAM-B) is a multifunctional transmembrane protein, which belongs to the immunoglobulin superfamily (IgSF). JAM-B is localized to cell-cell contacts and enriched at cell junctions in epithelial and endothelial cells, as well as on the surface of erythrocytes, leukocytes, and platelets. Recent research in this field has shown that JAM-B plays an important role in numerous cellular processes, such as tight junction assembly, spermatogenesis, regulation of paracellular permeability, leukocytic transmigration, angiogenesis, tumor metastasis and cell proliferation. This study provides a new research direction for the diagnosis and treatment of relevant diseases. In this review, we briefly focus on what is currently known about the structure, function, and mechanism of JAM-B, with particular emphasis on cancer.
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Affiliation(s)
- HUISHAN ZHAO
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Capital Medical university, Beijing 100069, P.R. China
- Cancer Institute of Capital Medical university, Beijing 100069, P.R. China
- Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
- Cardiff-China Medical Research Collaborative, Cardiff university School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - HEFEN YU
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Capital Medical university, Beijing 100069, P.R. China
- Cancer Institute of Capital Medical university, Beijing 100069, P.R. China
- Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - TRACEY A. MARTIN
- Cardiff-China Medical Research Collaborative, Cardiff university School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - XU TENG
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Capital Medical university, Beijing 100069, P.R. China
- Cancer Institute of Capital Medical university, Beijing 100069, P.R. China
- Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
- Cardiff-China Medical Research Collaborative, Cardiff university School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - WEN G. JIANG
- Cancer Institute of Capital Medical university, Beijing 100069, P.R. China
- Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
- Cardiff-China Medical Research Collaborative, Cardiff university School of Medicine, Heath Park, Cardiff CF14 4XN, UK
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41
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Baker OJ. Current trends in salivary gland tight junctions. Tissue Barriers 2016; 4:e1162348. [PMID: 27583188 DOI: 10.1080/21688370.2016.1162348] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 02/28/2016] [Accepted: 03/01/2016] [Indexed: 12/21/2022] Open
Abstract
Tight junctions form a continuous intercellular barrier between epithelial cells that is required to separate tissue spaces and regulate selective movement of solutes across the epithelium. They are composed of strands containing integral membrane proteins (e.g., claudins, occludin and tricellulin, junctional adhesion molecules and the coxsackie adenovirus receptor). These proteins are anchored to the cytoskeleton via scaffolding proteins such as ZO-1 and ZO-2. In salivary glands, tight junctions are involved in polarized saliva secretion and barrier maintenance between the extracellular environment and the glandular lumen. This review seeks to provide an overview of what is currently known, as well as the major questions and future research directions, regarding tight junction expression, organization and function within salivary glands.
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Affiliation(s)
- Olga J Baker
- School of Dentistry, University of Utah , Salt Lake City, UT, USA
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Liu C, Wang M, Jiang S, Wang L, Chen H, Liu Z, Qiu L, Song L. A novel junctional adhesion molecule A (CgJAM-A-L) from oyster (Crassostrea gigas) functions as pattern recognition receptor and opsonin. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2016; 55:211-220. [PMID: 26434620 DOI: 10.1016/j.dci.2015.09.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/29/2015] [Accepted: 09/29/2015] [Indexed: 06/05/2023]
Abstract
Junctional adhesion molecule (JAM), a subfamily of immunoglobulin superfamily (IgSF) with a couple of immunoglobulin domains, can act as regulator in homeostasis and inflammation of vertebrates. In the present study, a structural homolog of JAM-A (designated CgJAM-A-L) was screened out from oyster, Crassostrea gigas, through a search of JAM-A D1 domain (N-terminal Ig domain in JAM-A). The cDNA of CgJAM-A-L was of 1188 bp encoding a predicted polypeptide of 395 amino acids. The immunoreactive area of CgJAM-A-L mainly distributed over the plasma membrane of hemocytes. After Vibro splendidus or tumor necrosis factor (CgTNF-1) stimulation, the mRNA transcripts of CgJAM-A-L in hemocytes increased significantly by 4.46-fold and 9.00-fold (p < 0.01) of those in control group, respectively. The recombinant CgJAM-A-L protein (rCgJAM-A-L) could bind multiple PAMPs including lipopolysaccharides (LPS), peptidoglycan (PGN), lipoteichoic acid (LTA), mannose (MAN), β-glucan (GLU) and poly(I:C), and various microorganisms including Micrococcus luteus, Staphylococcus aureus, Escherichia coli, Vibro anguillarum, V. splendidus, Pastoris pastoris and Yarrowia lipolytica. The phagocytic rates of oyster hemocytes towards Gram-negative bacteria V. anguillarum and yeast P. pastoris were significantly enhanced after the incubation of rCgJAM-A-L, and even increased more significantly after the pre-incubation of rCgJAM-A-L with microbes (p < 0.01). The results collectively indicated that CgJAM-A-L functioned as an important pattern recognition receptor (PRR) and opsonin in the immune defense against invading pathogen in oyster. Moreover, as the most primitive specie with homolog of JAMs, the information of CgJAM-A-L in oyster would provide useful clues for the evolutionary study of JAMs and immunoglobulins.
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Affiliation(s)
- Conghui Liu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mengqiang Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Shuai Jiang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Lingling Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Hao Chen
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhaoqun Liu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Limei Qiu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Linsheng Song
- Key Laboratory of Mariculture & Stock Enhancement in North China's Sea, Ministry of Agriculture, Dalian Ocean University, Dalian 116023, China.
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Chen J, Xie ZR, Wu Y. Elucidating the general principles of cell adhesion with a coarse-grained simulation model. MOLECULAR BIOSYSTEMS 2016; 12:205-18. [DOI: 10.1039/c5mb00612k] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Coarse-grained simulation of interplay between cell adhesion and cell signaling.
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Affiliation(s)
- Jiawen Chen
- Department of Systems and Computational Biology
- Albert Einstein College of Medicine of Yeshiva University
- Bronx
- USA
| | - Zhong-Ru Xie
- Department of Systems and Computational Biology
- Albert Einstein College of Medicine of Yeshiva University
- Bronx
- USA
| | - Yinghao Wu
- Department of Systems and Computational Biology
- Albert Einstein College of Medicine of Yeshiva University
- Bronx
- USA
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Bhella D. The role of cellular adhesion molecules in virus attachment and entry. Philos Trans R Soc Lond B Biol Sci 2015; 370:20140035. [PMID: 25533093 PMCID: PMC4275905 DOI: 10.1098/rstb.2014.0035] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
As obligate intracellular parasites, viruses must traverse the host-cell plasma membrane to initiate infection. This presents a formidable barrier, which they have evolved diverse strategies to overcome. Common to all entry pathways, however, is a mechanism of specific attachment to cell-surface macromolecules or ‘receptors’. Receptor usage frequently defines viral tropism, and consequently, the evolutionary changes in receptor specificity can lead to emergence of new strains exhibiting altered pathogenicity or host range. Several classes of molecules are exploited as receptors by diverse groups of viruses, including, for example, sialic acid moieties and integrins. In particular, many cell-adhesion molecules that belong to the immunoglobulin-like superfamily of proteins (IgSF CAMs) have been identified as viral receptors. Structural analysis of the interactions between viruses and IgSF CAM receptors has not shown binding to specific features, implying that the Ig-like fold may not be key. Both proteinaceous and enveloped viruses exploit these proteins, however, suggesting convergent evolution of this trait. Their use is surprising given the usually occluded position of CAMs on the cell surface, such as at tight junctions. Nonetheless, the reason for their widespread involvement in virus entry most probably originates in their functional rather than structural characteristics.
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Affiliation(s)
- David Bhella
- Medical Research Council-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, 464 Bearsden Road, Glasgow G61 1QH, UK
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45
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Sumagin R, Parkos CA. Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration. Tissue Barriers 2015; 3:e969100. [PMID: 25838976 DOI: 10.4161/21688362.2014.969100] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 08/14/2014] [Indexed: 12/19/2022] Open
Abstract
Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function.
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Key Words
- AJs, adherens junctions
- CAR, coxsackie and adenovirus receptor
- CLMP, CAR-like protein
- CTLs, cytotoxic T lymphocytes
- CTX, thymocyte Xenopus
- DMs, Desmosomes
- Dsc-2, desmocollin-2
- Dsg-2, desmoglein-2
- E-cadherin, epithelial cadherin
- EGFR, Epithelial growth factor receptor
- EMT, epithelial-mesenchymal transition
- EpCAM, epithelial cell adhesion molecule
- IBD, inflammatory bowel diseases
- ICAM-1, intercellular adhesion molecule-1
- IECs, intestinal epithelial cells
- JAM, junctional adhesion molecules
- LAD, leukocyte adhesion deficiency
- LTB-4, lipid leukotriene B4
- MIP1 α, macrophage inflammatory protein 1 alpha
- MLCK, myosin light chain kinase
- MMPs, matrix metalloproteases
- NF-κB, nuclear factor kappa B
- NO, nitric oxide
- PARS, protease-activated receptors
- PI3K, phosphatidylinositol 3-kinase
- PMN, polymorphonuclear cells
- SGD, specific granule deficiency
- SIRPa, signal regulatory protein alpha
- TEM, transepithelial migration
- TGF-β, transforming growth factor beta
- TIAM1, metastasis-inducing protein 1
- TJs, tight junctions
- TSP-1, thrombospondin-1
- adhesion molecules
- barrier
- cell migration
- epithelial cells
- neutrophils
- sLea, sialyl Lewis A
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Affiliation(s)
- Ronen Sumagin
- Department of Pathology and Laboratory Medicine; Epithelial Pathobiology and Mucosal Inflammation Unit; Emory University ; Atlanta, GA USA
| | - Charles A Parkos
- Department of Pathology and Laboratory Medicine; Epithelial Pathobiology and Mucosal Inflammation Unit; Emory University ; Atlanta, GA USA
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Abstract
The tight junction is an important subcellular organelle which plays a vital role in epithelial barrier function. Claudin, as the integral membrane component of tight junctions, creates a paracellular transport pathway for various ions to be reabsorbed by the kidneys. This review summarizes advances in claudin structure, function and pathophysiology in kidney diseases. Different claudin species confer selective paracellular permeability to each of three major renal tubular segments: the proximal tubule, the thick ascending limb of Henle’s loop and the distal nephron. Defects in claudin function can cause a wide spectrum of kidney diseases, such as hypomagnesemia, hypercalciuria, kidney stones and hypertension. Studies using transgenic mouse models with claudin mutations have recapitulated several of these renal disease phenotypes and have elucidated the underlying biological mechanisms. Modern recording approaches based upon scanning ion conductance microscopy may resolve the biophysical nature of claudin transport function and provide novel insight into tight junction architecture.
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Affiliation(s)
- Jianghui Hou
- Washington University Renal Division, St. Louis, MO 63110, USA
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Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol 2014; 36:157-65. [PMID: 25171873 DOI: 10.1016/j.semcdb.2014.08.011] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 08/15/2014] [Accepted: 08/19/2014] [Indexed: 12/11/2022]
Abstract
The tight junction creates an intercellular barrier limiting paracellular movement of solutes and material across epithelia. Currently many proteins have been identified as components of the tight junction and understanding their architectural organization and interactions is critical to understanding the biology of the barrier. In general the architecture can be conceptualized into compartments with the transmembrane barrier proteins (claudins, occludin, JAM-A, etc.), linked to peripheral scaffolding proteins (such as ZO-1, afadin, MAGI1, etc.) which are in turned linked to actin and microtubules through numerous linkers (cingulin, myosins, protein 4.1, etc.). Within this complex network are associated many signaling proteins that affect the barrier and broader cell functions. The PDZ domain is a commonly used motif to specifically link individual junction protein pairs. Here we review some of the key proteins defining the tight junction and general themes of their organization with the perspective that much will be learned about function by characterizing the detailed architecture and subcompartments within the junction.
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Affiliation(s)
- Christina M Van Itallie
- The Laboratory of Tight Junction Structure and Function, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 50, Room 4525, 50 South Drive, Bethesda, MD 20892, USA.
| | - James M Anderson
- The Laboratory of Tight Junction Structure and Function, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 50, Room 4525, 50 South Drive, Bethesda, MD 20892, USA.
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Monteiro AC, Luissint AC, Sumagin R, Lai C, Vielmuth F, Wolf MF, Laur O, Reiss K, Spindler V, Stehle T, Dermody TS, Nusrat A, Parkos CA. Trans-dimerization of JAM-A regulates Rap2 and is mediated by a domain that is distinct from the cis-dimerization interface. Mol Biol Cell 2014; 25:1574-85. [PMID: 24672055 PMCID: PMC4019489 DOI: 10.1091/mbc.e14-01-0018] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Junctional adhesion molecule-A (JAM-A) is a tight junction–associated signaling protein that homodimerizes across cells at a unique motif to activate the small GTPase Rap2, previously implicated in the regulation of barrier function. JAM-A may therefore act as a barrier-inducing molecular switch that is activated when cells become confluent. Junctional adhesion molecule-A (JAM-A) is a tight junction–associated signaling protein that regulates epithelial cell proliferation, migration, and barrier function. JAM-A dimerization on a common cell surface (in cis) has been shown to regulate cell migration, and evidence suggests that JAM-A may form homodimers between cells (in trans). Indeed, transfection experiments revealed accumulation of JAM-A at sites between transfected cells, which was lost in cells expressing cis- or predicted trans-dimerization null mutants. Of importance, microspheres coated with JAM-A containing alanine substitutions to residues 43NNP45 (NNP-JAM-A) within the predicted trans-dimerization site did not aggregate. In contrast, beads coated with cis-null JAM-A demonstrated enhanced clustering similar to that observed with wild-type (WT) JAM-A. In addition, atomic force microscopy revealed decreased association forces in NNP-JAM-A compared with WT and cis-null JAM-A. Assessment of effects of JAM-A dimerization on cell signaling revealed that expression of trans- but not cis-null JAM-A mutants decreased Rap2 activity. Furthermore, confluent cells, which enable trans-dimerization, had enhanced Rap2 activity. Taken together, these results suggest that trans-dimerization of JAM-A occurs at a unique site and with different affinity compared with dimerization in cis. Trans-dimerization of JAM-A may thus act as a barrier-inducing molecular switch that is activated when cells become confluent.
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Affiliation(s)
- Ana C Monteiro
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Anny-Claude Luissint
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Ronen Sumagin
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Caroline Lai
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Franziska Vielmuth
- Institute of Anatomy and Cell Biology, Ludwig-Maximilians University, 80336 Munich, Germany
| | - Mattie F Wolf
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Oskar Laur
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Kerstin Reiss
- Interfaculty Institute of Biochemistry, University of Tübingen, D-72076 Tübingen, Germany
| | - Volker Spindler
- Institute of Anatomy and Cell Biology, Ludwig-Maximilians University, 80336 Munich, Germany
| | - Thilo Stehle
- Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN 37232Interfaculty Institute of Biochemistry, University of Tübingen, D-72076 Tübingen, Germany
| | - Terence S Dermody
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN 37232Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Asma Nusrat
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Charles A Parkos
- Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
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49
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Luissint AC, Nusrat A, Parkos CA. JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol 2014; 36:211-26. [PMID: 24667924 DOI: 10.1007/s00281-014-0421-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 02/25/2014] [Indexed: 02/06/2023]
Abstract
Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level, the mucosal barrier is regulated by tight junctions (TJs) that seal the paracellular space between adjacent epithelial cells. Transmembrane proteins within TJs include junctional adhesion molecules (JAMs) that belong to the cortical thymocyte marker for Xenopus family of proteins. JAM family encompasses three classical members (JAM-A, JAM-B, and JAM-C) and related molecules including JAM4, JAM-like protein, Coxsackie and adenovirus receptor (CAR), CAR-like membrane protein and endothelial cell-selective adhesion molecule. JAMs have multiple functions that include regulation of endothelial and epithelial paracellular permeability, leukocyte recruitment during inflammation, angiogenesis, cell migration, and proliferation. In this review, we summarize the current knowledge regarding the roles of the JAM family members in the regulation of mucosal homeostasis and leukocyte trafficking with a particular emphasis on barrier function and its perturbation during pathological inflammation.
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Affiliation(s)
- Anny-Claude Luissint
- Epithelial pathobiology and mucosal inflammation research unit, Department of Pathology and Laboratory Medicine, Emory University, 615 Michael Street, 30306, Atlanta, GA, USA
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Ebnet K. JAM-A and aPKC: A close pair during cell-cell contact maturation and tight junction formation in epithelial cells. Tissue Barriers 2014; 1:e22993. [PMID: 24665372 PMCID: PMC3879182 DOI: 10.4161/tisb.22993] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 11/15/2012] [Accepted: 11/21/2012] [Indexed: 12/19/2022] Open
Abstract
Cell-cell adhesion plays a critical role in the formation of barrier-forming epithelia. The molecules which mediate cell-cell adhesion frequently act as signaling molecules by recruiting and/or assembling cytoplasmic protein complexes. Junctional Adhesion Molecule (JAM)-A interacts with the cell polarity protein PAR-3, a member of the PAR-3-aPKC-PAR-6 complex, which regulates the formation of cell-cell contacts and the development of tight junctions (TJs). In our recent study we found that JAM-A is localized at primordial, spot-like cell-cell junctions (pAJs) in a non-phosphorylated form. After the recruitment of the PAR-aPKC complex and its activation at pAJs, aPKC phosphorylates JAM-A at Ser285 to promote the maturation of immature junctions. In polarized epithelial cells, aPKC phosphorylates JAM-A selectively at the TJs to maintain the barrier function of TJs. Thus, through mutual regulation, JAM-A and aPKC form a functional unit that regulates the establishment of barrier-forming junctions in vertebrate epithelial cells.
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Affiliation(s)
- Klaus Ebnet
- Institute-associated Research Group: Cell adhesion and cell polarity; Institute of Medical Biochemistry; Center of Molecular Biology of Inflammation; University Muenster; Muenster, Germany
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