doi: 10.1161/01.atv.0000102926.54780.e7
© 2003 American Heart Association, Inc.
Editorials |
JAM-1 Regulation of Endothelial Cell Migration: Implications for Angiogenesis
From the Department of Pharmacology, Lineberger Comprehensive Cancer Center and Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill.
Correspondence to Leslie V. Parise, Department of Pharmacology, University of North Carolina, CB#7365, Chapel Hill, NC 27599. E-mail parise{at}med.unc.edu
Angiogenesis, the sprouting of new blood vessels from existing ones, is a complex process that is critical to normal growth and development, but which occurs only in very specific conditions in adults. However, abnormal angiogenic responses can arise during development (eg, hemangioma formation) and in a variety of disease states. These diseases include, but are not limited to cancers in which blood vessels develop to support tumor growth, psoriasis, pulmonary hypertension, arthritis, and vascular retinopathy that can occur in diabetes, sickle cell disease, and other disorders. Multiple therapeutic approaches with varying degrees of success have been or are being developed to limit angiogenesis. Conversely, approaches to promote angiogenesis or the related but distinct process of collateral formation are also of interest for limiting ischemic damage in conditions where insufficient blood supply contributes to the condition or limits recovery, such as in myocardial infarction, stroke and other neurodegenerative conditions, Crohn disease, and others.1 Thus, advances in our understanding of events that occur at a molecular level to regulate blood vessel formation are of interest in providing future therapeutic targets to control these events.
See page 2165
Endothelial cells (ECs) form the innermost layer of most nacsent blood vessels (there are some exceptions, such as the cytotrophoblasts that line maternal arteries in the placenta2 and tumor cells that mimic ECs in some tumor blood vessels3). Angiogenesis involves an orchestration of events that include communication with and disruption of EC interaction with the surrounding extracellular matrix and neighboring cells; intracellular signaling; interplay between ECs, blood cells, and smooth muscle cells; and protease activity that releases matrix-bound angiogenic factors—events that lead to EC migration, proliferation, and establishment of new blood vessels. Similar elements are involved in blood vessel repair.
Adhesion molecules on ECs that contribute to vessel formation and stability include integrin 
vß3, which in several models appears to support vascularization associated with tumor growth in mice,4 rheumatoid arthritis in rabbits,5 and angiogenesis in a chick chorioallantoic membrane system.6 Complete absence of this integrin and the related vß5 during development may result in compensatory responses, however, because normal and pathological blood vessel development occur unabated in ß3/ß5-/- mice lacking both of these integrins.7 Endothelial cell-to-cell junctions are maintained by adherens junctions composed of molecules such as vascular endothelial (VE)-cadherin8 and ADAM159 and tight junctions comprising ZO-1, a member of the membrane-associated guanylate kinases family, claudins, occludins,10 and members of the immunoglobulin (Ig) superfamily of adhesion receptors, such as junctional adhesion molecule-1 (JAM-1).11 In addition to their adhesive functions, some of these transmembrane proteins, including JAM-1 and vß3, transduce signals that regulate EC behavior in angiogenic assays12–14
Jam-1 is a single-chain, type-1 transmembrane receptor most closely related to JAM-2 and JAM-3, which together are part of a larger subfamily of Ig adhesion receptors called the cortical thymocyte Xenopus family.15,16 The JAMs contain 2 extracellular Ig-like domains and have molecular weights ranging from 36 to 45 kDa. While JAM-1 is more widely distributed, being found on platelets, ECs, epithelial cells, and neutrophils, JAM-2 and JAM-3 are largely restricted to ECs.17,18 Like many other Ig adhesion receptors, JAM-1 binds in a homotypic fashion to JAM-1 on adjacent cells as well as to distinct ligands such as leukocyte Lß2.19 Before the sequence of JAM-1 was known, its first reported function was as a stimulatory molecule on platelets in response to bound antibodies, giving hint to its signal transduction capabilities.20 Moreover, JAM-1 (as well as JAM-2 and JAM-3) contains a canonical type-II, PDZ-domain-targeting motif that mediates binding to several proteins, such as ZO-1, occludin, and the cell-polarity protein protease-activated receptor 3 (PAR3).21–23 More recently, Naik et al14 showed that JAM-1 physically associates with vß3 when the ligand-binding site of vß3 is engaged by Arg-Gly-Asp-Ser (RGDS) peptide. These authors further demonstrated that JAM-1 is required for basic fibroblast growth factor (bFGF) signaling, because an antibody against the extracellular domain of JAM-1 or expression of JAM-1 with a mutated cytoplasmic domain prevent bFGF-induced EC proliferation, angiogenesis, mitogen-activated protein kinase activation, and EC tube formation. These results suggest that signaling through JAM-1 is key to bFGF-induced signaling.
In a study reported in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Naik et al24 extend these observations by using RNA interference to deplete endogenous JAM-1 in ECs. Expression of VE-cadherin, ZO-1, ß-catenin, and the ß3 integrin subunit were unaffected in these cells. However, both bFGF-independent and -dependent changes in cell behavior were observed. Even in the absence of bFGF stimulation, membrane-associated actin was reduced in JAM-1–depleted cells without change in the localization of VE-cadherin or ZO-1. Moreover, basal cell adhesion to and spreading on vitronectin, both vß3-dependent events, were significantly diminished. Interestingly, adhesion to fibronectin was unaffected. Most notably, bFGF-stimulated migration on vitronectin, but not fibronectin, was inhibited, as measured in both a haptotactic migration assay and a wound or scrape assay of EC monolayers. As expected, the JAM-1–depleted cells lacked bFGF-induced ERK signaling, which is required for bFGF-induced migration on vitronectin. These results confirm that JAM-1 is critical to both bFGF signaling and vß3 function in endothelial cells and place JAM-1 as a candidate target for therapeutic modulation.
The work by Naik et al24 will likely lead to studies aimed at defining the role of JAM-1 in whole animal models replicating normal and aberrant blood vessel formation, as in tumerogenesis and other states discussed above. It will be interesting to learn whether acute inhibition of JAM-1 versus chronic loss of JAM-1 during development of JAM-1-/- mice will result in similar or distinct phenotypes, as in the ß3 and ß3/ß5-/- mice.7 The physical and functional connection between vß3 and JAM-1 may lead to an understanding of the current controversy surrounding the role of vß3 in angiogenesis. While blocking JAM-1 also blocks vß3 function, it is unknown whether the reverse occurs, ie, whether blocking vß3 also affects JAM-1 adhesive and signaling events. If so, such a scenario might explain why blocking preexisting vß3 inhibits angiogenesis, whereas the lack of vß3 in ß3-/- mice enables an apparently normal angiogenic response. Perhaps the chronic loss of ß3 has no effect on JAM-1 function such that angiogenesis can proceed normally. While this notion is purely speculative and potential compensatory events in ß3 deficient mice may be complicated, it is apparent that a greater understanding of how JAM-1 regulates bFGF signaling, vß3 function, the function of other molecules involved in angiogenesis, and the signaling pathways involved will enhance our overall understanding of blood vessel formation. Such investigations are likely to uncover additional promising therapeutic targets for regulating angiogenic processes.
References
1. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003; 9: 653–660.[CrossRef][Medline] [Order article via Infotrieve]
2. Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher SJ. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol. 2002; 160: 1405–1423.
3. Hendrix MJ, Seftor EA, Kirschmann DA, Quaranta V, Seftor RE. Remodeling of the microenvironment by aggressive melanoma tumor cells. Ann N Y Acad Sci. 2003; 995: 151–161.[Medline] [Order article via Infotrieve]
4. Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA. Tumor regression by targeted gene delivery to the neovasculature. Science. 2002; 296: 2404–2407.
5. Storgard CM, Stupack DG, Jonczyk A, Goodman SL, Fox RI, Cheresh DA. Decreased angiogenesis and arthritic disease in rabbits treated with an vß3 antagonist. J Clin Invest. 1999; 103: 47–54.[Medline]
[Order article via Infotrieve]
6. Tsopanoglou NE, Andriopoulou P, Maragoudakis ME. On the mechanism of thrombin-induced angiogenesis: involvement of vß3-integrin. Am J Physiol Cell Physiol. 2002; 283: C1501–C1510.
7. Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO, Hodivala-Dilke KM. Enhanced pathological angiogenesis in mice lacking ß3 integrin or ß3 and ß5 integrins. Nat Med. 2002; 8: 27–34.[CrossRef][Medline] [Order article via Infotrieve]
8. Lampugnani MG, Corada M, Caveda L, Breviario F, Ayalon O, Geiger B, Dejana E. The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, ß-catenin, and -catenin with vascular endothelial cadherin (VE-cadherin). J Cell Biol. 1995; 129: 203–217.
9. Ham C, Levkau B, Raines EW, Herren B. ADAM15 is an adherens junction molecule whose surface expression can be driven by VE-cadherin. Exp Cell Res. 2002; 279: 239–247.[CrossRef][Medline] [Order article via Infotrieve]
10. Tsukita S, Furuse M. Occludin and claudins in tight-junction strands: leading or supporting players? Trends Cell Biol. 1999; 9: 268–273.[CrossRef][Medline] [Order article via Infotrieve]
11. Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E. 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.
12. Eliceiri BP, Klemke R, Stromblad S, Cheresh DA. Integrin vß3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J Cell Biol. 1998; 140: 1255–1263.
13. Stromblad S, Becker JC, Yebra M, Brooks PC, Cheresh DA. Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin vß3 during angiogenesis. J Clin Invest. 1996; 98: 426–433.[Medline]
[Order article via Infotrieve]
14. Naik MU, Mousa SA, Parkos CA, Naik UP. Signaling through JAM-1 and vß3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and vß3 complex. Blood. 2003; 102: 2108–2114.
15. Chretien I, Robert J, Marcuz A, Garcia-Sanz JA, Courtet M, Du PL. CTX, a novel molecule specifically expressed on the surface of cortical thymocytes in Xenopus. Eur J Immunol. 1996; 26: 780–791.[Medline] [Order article via Infotrieve]
16. Aurrand-Lions MA, Duncan L, Du PL, Imhof BA. Cloning of JAM-2 and JAM-3: an emerging junctional adhesion molecular family? Curr Top Microbiol Immunol. 2000; 251: 91–98.[Medline] [Order article via Infotrieve]
17. Palmeri D, van Zante A, Huang CC, Hemmerich S, Rosen SD. 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.
18. Ebnet K, Aurrand-Lions M, Kuhn A, Kiefer F, Butz S, Zander K, Brickwedde MK, Suzuki A, Imhof BA, Vestweber D. 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.
19. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002; 3: 151–158.[CrossRef][Medline] [Order article via Infotrieve]
20. Naik UP, Ehrlich YH, Kornecki E. 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 (Pt 1): 155–162.
21. Bazzoni G, Martinez-Estrada OM, Orsenigo F, Cordenonsi M, Citi S, Dejana E. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem. 2000; 275: 20520–20526.
22. Ebnet K, Schulz CU, Meyer Zu Brickwedde MK, Pendl GG, Vestweber D. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J Biol Chem. 2000; 275: 27979–27988.
23. Itoh M, Sasaki H, Furuse M, Ozaki H, Kita T, Tsukita S. Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctions. J Cell Biol. 2001; 154: 491–497.
24. Naik MU, Vuppalanchi D, Naik UP. Essential role of junctional adhesion molecule-1 in basic fibroblast growth factor-induced endothelial cell migration. Arterioscler Thromb Vasc Biol. 2003; 23: 2165–2171.
This article has been cited by other articles:
 |
|
 |
|
  A. Zernecke, E. A. Liehn, L. Fraemohs, P. von Hundelshausen, R. R. Koenen, M. Corada, E. Dejana, and C. Weber Importance of Junctional Adhesion Molecule-A for Neointimal Lesion Formation and Infiltration in Atherosclerosis-Prone Mice Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): e10 - e13. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||