Regulation of vascular endothelial permeability by junctional adhesion molecules (JAM)

Summary

The vascular endothelium forms a barrier between the circulation and the interstitium, and changes in vascular permeability are very important during vascular repair and inflammatory conditions. The regulation of the endothelial barrier depends on actomyosin- related cell contractility as well as the integrity of cellcell junctions, such as tight and adherens junctions.The present review will introduce the basic pathways involved in the regulation of the endothelial barrier as well as important participating signaling players, such as the small GTPases RhoA, Rac and Rap1. In this context, we will attempt to analyze and interpret the recent evidence pointing to the role of the family of junctional adhesion molecules (JAMs) in modulating the pathways involved in the regulation of the endothelial barrier.

Keywords

Adhesion molecules - cadherins - endothelial cells - inflammation - GTPases

• References

• 1 Wojciak-Stothard B, Ridley AJ. Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol 2002; 39: 187-199.
• 2 Blum MS. et al. Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines. Am J Physiol 1997; 273: H286-294.
• 3 Kelly JJ. et al. Pulmonary microvascular and macrovascular endothelial cells: differential regulation of Ca2+ and permeability. Am J Physiol 1998; 274: L810-819.
• 4 Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 2004; 84: 869-901.
• 5 Dejana E. et al. The molecular organization of endothelial junctions and their functional role in vascular morphogenesis and permeability. Int J Dev Biol 2000; 44: 743-748.
• 6 Mehta D, Malik AB. Signaling mechanisms regulating endothelial permeability. Physiol Rev 2006; 86: 279-367.
• 7 de Rooij J. et al. Epac is a Rap1 guanine-nucleotideexchange factor directly activated by cyclic AMP. Nature 1998; 396: 474-477.
• 8 Kopperud R. et al. cAMP effector mechanisms. Novel twists for an ‘old’ signaling system. FEBS Lett 2003; 546: 121-126.
• 9 Saha C. et al. Expanding role of G proteins in tight junction regulation: Galpha(s) stimulates TJ assembly. Biochem Biophys Res Commun 2001; 285: 250-256.
• 10 van Nieuw Amerongen GP. et al. Involvement of RhoA/Rho kinase signaling in VEGF-induced en-dothelial cell migration and angiogenesis in vitro. Arterioscler Thromb Vasc Biol 2003; 23: 211-217.
• 11 Lampugnani MG. et al. VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam. Mol Biol Cell 2002; 13: 1175-1189.
• 12 Kawano Y. et al. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol 1999; 147: 1023-1038.
• 13 van Nieuw Amerongen GP. et al. Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases. Circ Res 2000; 87: 335-340.
• 14 Wojciak-Stothard B. et al. Rho and Rac but not Cdc42 regulate endothelial cell permeability. J Cell Sci 2001; 114: 1343-1355.
• 15 Eriksson A. et al. Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation 2003; 107: 1532-1538.
• 16 Kouklis P. et al. Cdc42 regulates the restoration of endothelial barrier function. Circ Res 2004; 94: 159-166.
• 17 Zenke FT. et al. Identification of a central phosphorylation site in p21-activated kinase regulating autoinhibition and kinase activity. J Biol Chem 1999; 274: 32565-32573.
• 18 Goeckeler ZM. et al. Phosphorylation of myosin light chain kinase by p21-activated kinase PAK2. J Biol Chem 2000; 275: 18366-18374.
• 19 Edwards DC. et al. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1999; 1: 253-259.
• 20 Kiosses WB. et al. A role for p21-activated kinase in endothelial cell migration. J Cell Biol 1999; 147: 831-844.
• 21 Stockton RA. et al. p21-activated kinase regulates endothelial permeability through modulation of contractility. J Biol Chem 2004; 279: 46621-46630.
• 22 Orr AW. et al. Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis. J Cell Biol 2007; 176: 719-727.
• 23 Gavard J, Gutkind JS. VEGF controls endothelialcell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006; 8: 1223-1234.
• 24 Cullere X. et al. Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Blood 2005; 105: 1950-1955.
• 25 Fukuhara S. et al. Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac- Rap1 signaling pathway. Mol Cell Biol 2005; 25: 136-146.
• 26 Kooistra MR. et al. Epac1 regulates integrity of endothelial cell junctions through VE-cadherin. FEBS Lett 2005; 579: 4966-4972.
• 27 Wittchen ES. et al. Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. J Biol Chem 2005; 280: 11675-11682.
• 28 Bos JL. et al. The role of Rap1 in integrin-mediated cell adhesion. Biochem Soc Trans 2003; 31: 83-86.
• 29 Bos JL. Epac: a new cAMP target and new avenues in cAMP research. Nat Rev Mol Cell Biol 2003; 4: 733-738.
• 30 Orlova VV. et al. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts. J Exp Med 2006; 203: 2703-2714.
• 31 Hogan C. et al. Rap1 regulates the formation of E-cadherin-based cell-cell contacts. Mol Cell Biol 2004; 24: 6690-670206.
• 32 Price LS. et al. Rap1 regulates E-cadherin-mediated cell-cell adhesion. J Biol Chem 2004; 279: 35127-35132.
• 33 Fukuyama T. et al. Involvement of the c-Src-Crk- C3G-Rap1 signaling in the nectin-induced activation of Cdc42 and formation of adherens junctions. J Biol Chem 2005; 280: 815-825.
• 34 Sakurai A. et al. MAGI-1 is required for Rap1 activation upon cell-cell contact and for enhancement of vascular endothelial cadherin-mediated cell adhesion. Mol Biol Cell 2006; 17: 966-976.
• 35 Williams AF, Barclay AN. The immunoglobulin superfamily--domains for cell surface recognition. Annu Rev Immunol 1988; 6: 381-405.
• 36 Bazzoni G. The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 2003; 15: 525-530.
• 37 Chavakis T. et al. Leukocyte transendothelial migration: JAMs add new pieces to the puzzle. Thromb Haemost 2003; 89: 13-17.
• 38 Kornecki E. et al. Activation of human platelets by a stimulatory monoclonal antibody. J Biol Chem 1990; 265: 1020642-1020648.
• 39 Naik UP. et al. Mechanisms of platelet activation by a stimulatory antibody: cross-linking of a novel platelet receptor for monoclonal antibody F11 with the Fc gamma RII receptor. Biochem J 1995; 310: 155-162.
• 40 Sobocka MB. et al. Cloning of the human platelet F11 receptor: a cell adhesion molecule member of the immunoglobulin superfamily involved in platelet aggregation. Blood 2000; 95: 260206-2609.
• 41 Palmeri D. et al. Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J Biol Chem 2000; 275: 19139-19145.
• 42 Aurrand-Lions M. et al. Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of the three JAM family members. Blood 2001; 98: 3699-3707.
• 43 Aurrand-Lions M. et al. JAM-2, a novel immunoglobulin superfamily molecule, expressed by endothelial and lymphatic cells. J Biol Chem 2001; 276: 2733-2741.
• 44 Keiper T. et al. The role of junctional adhesion molecule- C (JAM-C) in oxidized LDL-mediated leukocyte recruitment. Faseb J 2005; 19: 2078-2080.
• 45 Chavakis T. et al. The junctional adhesion molecule- C promotes neutrophil transendothelial migration in vitro and in vivo. J Biol Chem 2004; 279: 55602-55608.
• 46 Santoso S. et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 2002; 196: 679-691.
• 47 Johnson-Leger CA. et al. Junctional adhesion molecule- 2 (JAM-2) promotes lymphocyte transendothelial migration. Blood 2002; 10206: 2479-2486.
• 48 Ody C. et al. Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies. Leukemia 202067; Epub ahead of print.
• 49 Ebnet K. et al. Junctional adhesion molecules (JAMs): more molecules with dual functions?. J Cell Sci 2004; 7: 19-29.
• 50 Arrate MP. et al. Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 2001; 76: 45826-45832.
• 51 Liang TW. et al. Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts with T, NK, and dendritic cells through JAM 3. J Immunol 2002; 168: 1618-1626.
• 52 Santoso S. et al. The homophilic binding of junctional adhesion molecule-C mediates tumor cell-endothelial cell interactions. J Biol Chem 2005; 280: 36326-36333.
• 53 Ostermann G. et al. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 2002; 3: 151-158.
• 54 Fraemohs L. et al. The functional interaction of the beta 2 integrin lymphocyte function-associated antigen-1 with junctional adhesion molecule-A is mediated by the I domain. J Immunol 2004; 173: 6259-6264.
• 55 Cunningham SA. et al. JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem 2002; 277: 27589-27592.
• 56 Zen K. et al. JAM-C is a component of desmosomes and a ligand for CD11b/CD18-mediated neutrophil transepithelial migration. Mol Biol Cell 2004; 15: 3926-3937.
• 57 Lamagna C. et al. Dual interaction of JAM-C with JAM-B and alpha(M)beta2 integrin: function in junctional complexes and leukocyte adhesion. Mol Biol Cell 2005; 16: 4992-502063.
• 58 Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol, 2004; 4: 432-444.
• 59 Aurrand-Lions M. et al. Junctional adhesion molecule- C regulates the early influx of leukocytes into tissues during inflammation. J Immunol 2005; 174: 6406-6415.
• 60 Vonlaufen A. et al. The role of junctional adhesion molecule C (JAM-C) in acute pancreatitis. J Pathol 2006; 209: 540-548.
• 61 Khandoga A. et al. Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration. Blood 2005; 106: 725-733.
• 62 Corada M. et al., Junctional adhesion molecule- A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury. Proc Natl Acad Sci USA 2005; 102: 10634-10639.
• 63 Zernecke A. et al. Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. Arterioscler Thromb Vasc Biol 2006; 26: 10-13.
• 64 Martin-Padura I. et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 1998; 142: 117-127.
• 65 Cunningham SA. et al. A novel protein with homology to the junctional adhesion molecule. Characterization of leukocyte interactions. J Biol Chem 2000; 275: 34750-34756.
• 66 Aurrand-Lions MA. et al. Cloning of JAM-2 and JAM-3: an emerging junctional adhesion molecular family?. Curr Top Microbiol Immunol 2000; 251: 91-98.
• 67 Ebnet K. et al. The cell polarity protein ASIP/ PAR-3 directly associates with junctional adhesion molecule (JAM). Embo J 2001; 20: 3738-3748.
• 68 Ebnet K. et al. The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity. J Cell Sci 2003; 116: 3879-3891.
• 69 Bazzoni G. et al. Homophilic interaction of junctional adhesion molecule. J Biol Chem 2000; 275: 30970-30976.
• 70 Babinska A. et al. Two regions of the human platelet F11-receptor (F11R) are critical for platelet aggregation, potentiation and adhesion. Thromb Haemost 2002; 87: 712-721.
• 71 Kostrewa D. et al. X-ray structure of junctional adhesion molecule: structural basis for homophilic adhesion via a novel dimerization motif. Embo J 2001; 20: 4391-4398.
• 72 Bazzoni G. et al. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem 2000; 275: 20520-20526.
• 73 Ebnet K. et al. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J Biol Chem 2000; 275: 27979-27988.
• 74 Hamazaki Y. et al. Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. J Biol Chem 2002; 277: 455-461.
• 75 Joberty G. et al. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2000; 2: 531-53.
• 76 Gliki G. et al. Spermatid differentiation requires the assembly of a cell polarity complex downstream of junctional adhesion molecule-C. Nature 2004; 431: 320-324.
• 77 Mandicourt G. et al. JAM-C regulates tight junctions and integrin-mediated cell adhesion and migration. J Biol Chem, 2007; 282: 1830-1837.
• 78 Liao F. et al. Migration of monocytes across endothelium and passage through extracellular matrix involve separate molecular domains of PECAM-1. J Exp Med 1995; 182: 1337-1343.
• 79 Liu Y. et al. Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci 2000; 113: 2363-2374.
• 80 Mandell KJ. et al. Junctional adhesion molecule 1 regulates epithelial cell morphology through effects on beta1 integrins and Rap1 activity. J Biol Chem 2005; 280: 11665-11674.
• 81 Mandell KJ. et al. Antibody blockade of junctional adhesion molecule-A in rabbit corneal endothelial tight junctions produces corneal swelling. Invest Ophthalmol Vis Sci 2006; 47: 2408-2416.
• 82 Ostermann G. et al. Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium: inhibition by soluble JAM-A. Arterioscler Thromb Vasc Biol 2005; 25: 729-735.
• 83 Naik MU. et al. Essential role of junctional adhesion molecule-1 in basic fibroblast growth factor-induced endothelial cell migration. Arterioscler Thromb Vasc Biol 2003; 23: 2165-2171.
• 84 Cooke VG. et al. Fibroblast growth factor-2 failed to induce angiogenesis in junctional adhesion molecule- A-deficient mice. Arterioscler Thromb Vasc Biol 2006; 26: 202065-2011.
• 85 Lamagna C. et al. Antibody against junctional adhesion molecule-C inhibits angiogenesis and tumor growth. Cancer Res 2005; 65: 5703-5710.
• 86 Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 2005; 6: 622-634.
• 87 Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol 2003; 4: 225-236.
• 88 Bos JL. et al. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2001; 2: 369-377.
• 89 Mandell KJ. et al. Involvement of the junctional adhesion molecule-1 (JAM1) homodimer interface in regulation of epithelial barrier function. J Biol Chem 2004; 279: 16254-16262.
• 90 Hoshino T. et al. Regulation of E-cadherin endocytosis by nectin through afadin, Rap1, and p120ctn. J Biol Chem 2005; 280: 24095-24103.
• 91 Zhang Z. et al. AF6 negatively regulates Rap1-induced cell adhesion. J Biol Chem 2005; 280: 3320206-33205.
• 92 Boettner B. et al. The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin. Proc Natl Acad Sci USA 2000; 97: 9064-9069.