JAM-2, a Novel Immunoglobulin Superfamily Molecule, Expressed by Endothelial and Lymphatic Cells

Abstract

Cell-cell contacts are essential for morphogenesis and tissue function and play a vital role in mediating endothelial cohesion within the vascular system during vessel growth and organization. We identified a novel junctional adhesion molecule, named JAM-2, by a selective RNA display method, which allowed identification of transcripts encoding immunoglobulin superfamily molecules regulated during coculture of endothelial cells with tumor cells. The JAM-2 transcript is highly expressed during embryogenesis and is detected in lymph node and Peyer's patches RNA of adult mice. Accordingly, antibodies specific for JAM-2 stain high endothelial venules and lymphatic vessels in lymphoid organs, and vascular structures in the kidney. Using real time video microscopy, we show that JAM-2 is localized within minutes to the newly formed cell-cell contact. The role of the protein in the sealing of cell-cell contact is further suggested by the reduced paracellular permeability of cell monolayer transfected with JAM-2 cDNA, and by the localization of JAM-2 to tight junctional complexes of polarized cells. Taken together, our results suggest that JAM-2 is a novel vascular molecule, which participates in interendothelial junctional complexes. Cell-cell contacts are essential for morphogenesis and tissue function and play a vital role in mediating endothelial cohesion within the vascular system during vessel growth and organization. We identified a novel junctional adhesion molecule, named JAM-2, by a selective RNA display method, which allowed identification of transcripts encoding immunoglobulin superfamily molecules regulated during coculture of endothelial cells with tumor cells. The JAM-2 transcript is highly expressed during embryogenesis and is detected in lymph node and Peyer's patches RNA of adult mice. Accordingly, antibodies specific for JAM-2 stain high endothelial venules and lymphatic vessels in lymphoid organs, and vascular structures in the kidney. Using real time video microscopy, we show that JAM-2 is localized within minutes to the newly formed cell-cell contact. The role of the protein in the sealing of cell-cell contact is further suggested by the reduced paracellular permeability of cell monolayer transfected with JAM-2 cDNA, and by the localization of JAM-2 to tight junctional complexes of polarized cells. Taken together, our results suggest that JAM-2 is a novel vascular molecule, which participates in interendothelial junctional complexes. superfamily junctional adhesion molecule Chinese hamster ovary polymerase chain reaction enhanced green fluorescent protein enzyme-linked immunosorbent assay fluorescein isothiocyanate low density lipoprotein high endothelial venule Madin-Darby canine kidney phosphate-buffered saline expressed sequence tag Confluency Regulated Adhesion Molecules monoclonal antibody polyacrylamide gel electrophoresis Platelet Endothelial Cell Adhesion Molecule 2,2'-Azino-Bis (3-ethybenz Thiazoline 6-Sulfonic acid) diammonium Adhesion molecules play essential roles in the overall tissue organization and the proper physiological function of organs by establishing and organizing cell-cell contacts (1Gumbiner B.M. Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2948) Google Scholar). The function of endothelial cells lining the vessel walls relies in part on their ability to express different adhesion molecules in a coordinated and regulated way. It has been demonstrated that endothelial cells regulate vascular permeability and leukocyte emigration from the blood into the surrounding tissues. Leukocyte emigration occurs in a multistep adhesion process involving different classes of adhesion molecules, namely selectins, integrins, and cell adhesion molecules of the immunoglobulin superfamily (Ig Sf)1 (2Butcher E.C. Cell. 1991; 67: 1033-1036Abstract Full Text PDF PubMed Scopus (2530) Google Scholar, 3Springer T. Nature. 1990; 346: 425-434Crossref PubMed Scopus (5860) Google Scholar, 4Lasky L.A. Science. 1992; 258: 964-969Crossref PubMed Scopus (1153) Google Scholar). The members of the Ig Sf possess structural domains similar to the variable (V type) or constant (C type) immunoglobulin domains found in T or B cell receptor (5Willams A.F. Barclay A.N. Annu. Rev. Immunol. 1988; 6: 381-405Crossref PubMed Scopus (1791) Google Scholar, 6Du Pasquier L. Courtet M. Chretien I. Eur. J. Immunol. 1999; 29: 1729-1739Crossref PubMed Scopus (17) Google Scholar). JAM (hereafter referred to as JAM-1), a recently described immunoglobulin superfamily molecule with two VH domains, was shown to regulate monocyte transmigration across endothelial cell layers (7Malergue F. Galland F. Martin F. Mansuelle P. Aurrand-Lions M. Naquet P. Mol. Immunol. 1998; 35: 1111-1119Crossref PubMed Scopus (87) Google Scholar, 8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar). The protein specifically localizes to tight junctions of epithelial and endothelial cells, indicating that molecules participating in intercellular junctions may regulate vascular functions (9Telo P. Lostaglio S. Dejana E. Therapie. 1997; 52: 395-398PubMed Google Scholar, 10Dejana E. Zanetti A. Del Maschio A. Haemostasis. 1996; 26 Suppl. 4: 210-219PubMed Google Scholar). To date, the cell surface molecules known to participate specifically in tight junctions include JAM-1, occludin, and the claudins (8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar, 11Furuse M. Hirase T. Itoh M. Nagafuchi A. Yonemura S. Tsukita S. J. Cell Biol. 1993; 123: 1777-1788Crossref PubMed Scopus (2143) Google Scholar, 12Furuse M. Fujita K. Hiiragi T. Fujimoto K. Tsukita S. J. Cell Biol. 1998; 141: 1539-1550Crossref PubMed Scopus (1730) Google Scholar). JAM-1 and occludin are expressed by both endothelial and epithelial cells, while some members of the claudin family display tissue-specific distribution (7Malergue F. Galland F. Martin F. Mansuelle P. Aurrand-Lions M. Naquet P. Mol. Immunol. 1998; 35: 1111-1119Crossref PubMed Scopus (87) Google Scholar, 13Morita K. Furuse M. Fujimoto K. Tsukita S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 511-516Crossref PubMed Scopus (983) Google Scholar, 14Hirase T. Staddon J.M. Saitou M. Ando-Akatsuka Y. Itoh M. Furuse M. Fujimoto K. Tsukita S. Rubin L.L. J. Cell Sci. 1997; 110: 1603-1613Crossref PubMed Google Scholar). Interestingly, claudin-5 was found in the tight junctions of endothelial cells (15Morita K. Sasaki H. Furuse M. Tsukita S. J. Cell Biol. 1999; 147: 185-194Crossref PubMed Scopus (700) Google Scholar), whereas claudin-11 was present in tight junctions of myelin sheaths in the brain and sertoli cells in the testis (16Morita K. Sasaki H. Fujimoto K. Furuse M. Tsukita S. J. Cell Biol. 1999; 145: 579-588Crossref PubMed Scopus (377) Google Scholar), reflecting some heterogeneity in the molecular composition of tight junctions found in different cellular system (17Gow A. Southwood C.M. Li J.S. Pariali M. Riordan G.P. Brodie S.E. Danias J. Bronstein J.M. Kachar B. Lazzarini R.A. Cell. 1999; 99: 649-659Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar). This suggests that the function of tight junctions and their regulation may involve specific expression of junctional proteins or distinct activation events, which regulate the stability of tight junctions (18Anderson J.M. Balda M.S. Fanning A.S. Curr. Opin. Cell. Biol. 1993; 5: 772-778Crossref PubMed Scopus (181) Google Scholar). Hence, we started to search for novel surface molecules of the Ig Sf, which may be more specific for vascular endothelium than JAM-1. We took advantage of the fact that blood vessels in tumors are often leaky, indicating that the barrier function of angiogenic endothelial cells may be lost, due to regulation of tight junctional molecules in endothelial cells growing in the of tumor cells E. J.S. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, L.A. J. 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The cell cells, cells, and cell from the cells, in with and from cells in as cells by with and by a in cells with cells for in tissue and cells the in RNA was in with the The was from of and The and the of by of on of specific for the We the with the and encoding for the in and The as of cDNA, of of of of of of of polymerase The for the as and for was and for The on a polyacrylamide gel and was expressed from the polyacrylamide and by and as described P. Science. 1992; PubMed Scopus Google Scholar). The of of The of into of two the and the system The was to encoding for a Ig superfamily molecule and and the sequence was by of on the of the of The sequence for JAM-2 was in the from the of and the the The encoding JAM-1 was by P. Naquet The the fluorescent and the system sequence the on the and from cells or was to was from of RNA with the was from and The from and the encoding for the immunoglobulin domains of JAM-1 and JAM-2, or the sequence for was in The and on The sequence encoding was from P. H. and into and named The found in the sequence the of JAM-2 and JAM-1, to the two the of the in The encoding JAM-2 or JAM-1 from or The in by and further or This in for JAM-2 and for JAM-1. The of cells was as described C. B. J. Cell Sci. 1998; Google Scholar). for permeability by growing transfected cells for in and for by and localization by video was and for To molecules, the sequence encoding domains of JAM-1 or JAM-2 by from the and for JAM-1, or and for The by to the in with sequence in as described C. 1999; Google Scholar). The of was by the on both cells transfected method, and a of of the molecules or was on a and was by and The monoclonal antibodies (7Malergue F. Galland F. Martin F. Mansuelle P. Aurrand-Lions M. Naquet P. Mol. Immunol. 1998; 35: 1111-1119Crossref PubMed Scopus (87) Google L. P. Eur. J. Immunol. 1993; PubMed Scopus Google Scholar), M.S. J. Cell Biol. PubMed Scopus Google Scholar), and Cell. 35: Full Text PDF PubMed Scopus Google Scholar). The of antibodies JAM-2 was in the and molecule as in M. Galland F. H. Naquet P. 1996; 5: Full Text Full Text PDF PubMed Scopus Google Scholar). of JAM-2 molecule with was to a of of to cells, and in by for the of specifically with antibody in for with and for with of transfected cells. with to the and for antibodies detected and a and and by on cells transfected with encoding or antibodies of or which is of the on protein to the was for and for was to or for and with in with the antibodies and with the to the of endothelial cells, of was to J. Cell Biol. 99: PubMed Scopus Google Scholar). The cells for with with to JAM-1 or JAM-2, and was for and cells with and JAM-1 or JAM-2 expression was on cells for the two endothelial cell and by as described M. M. Naquet P. Cell Immunol. 1997; PubMed Scopus Google for and to the proteins to and of the in with of and for to of the proteins of and of and was by to and with was transfected or cells to on for with the was for in the and in the was in the and was in the The of was and and To the of with cells was as the coculture of endothelial cells with tumor cells, endothelial are by of adhesion molecules L. A. J. PubMed Scopus Google Scholar). a is to search for novel regulated adhesion molecules by to the of of RNA we the to transcripts encoding adhesion molecules of the Ig we the encoding molecules with This was by the of domains of Ig Sf adhesion molecules and the identification of a surrounding the participating to the we the of the to the for The of and different was to the of a The display of with different is shown on A. The of the from from the endothelial cell from the of endothelial and tumor cell or from the tumor cell allowed the of expressed and the that and for and The of the two and as for of novel Ig Sf transcripts a the sequence of the sequence the and and to the of the with sequence in the of the and the was by a of shown in the sequence encoding a protein of of a molecular of for the The was by a that may be and H. J. S. 1997; PubMed Scopus Google Scholar). The protein was of a protein VH and immunoglobulin the sequence of the for the of the and and of the protein sequence with sequence identified the tight junctional JAM-1 (8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar), as the sequence with the protein The transcript to the was named The in the part of the molecules to the participating in the of the Ig domains (5Willams A.F. Barclay A.N. Annu. Rev. Immunol. 1988; 6: 381-405Crossref PubMed Scopus (1791) Google Scholar), and to surrounding the the of or the within the Interestingly, two are found within the of JAM-2, while are from the JAM-1 the of are the the and the of the The tissue distribution of JAM-2 transcript was by and with JAM-1 The JAM-2 transcript was highly expressed in tissue and in Peyer's lymph and testis of adult of was detected in The expression of the JAM-2 transcript was low in and The of JAM-1 and JAM-2 during the encoding JAM-2 was as as whereas JAM-1 was detected during This suggested that the JAM-2 transcript be expressed in with expression in in adult tissues. To the expression of JAM-2 in more we a of monoclonal antibodies a of JAM-2 The of was by on of JAM-1 and specifically To further the of the was on cells transfected with or proteins of JAM-1 or JAM-2 results the of the for JAM-2 and the of on JAM-1 transfected cells, which specifically by the described (7Malergue F. Galland F. Martin F. Mansuelle P. Aurrand-Lions M. Naquet P. Mol. Immunol. 1998; 35: 1111-1119Crossref PubMed Scopus (87) Google Scholar). we of JAM-2 expression on kidney and lymph node the the of the a of structures was with in with whereas or the epithelial cells We our on the of the kidney and found a of structures with To vascular we and identified the vessels by their expression the of interendothelial was detected antibodies to JAM-2, JAM-1, or and lymph node the high endothelial venules The expressed JAM-1, and and with in the localization of the the of the lymph antibodies cells in which to cells of lymphatic the with to be to lymphatic vessels and a of endothelial of JAM-2, JAM-1, and of kidney or from lymph node with the or JAM-2 and JAM-1 and or and of with for the Using the was was the with antibody to be we to endothelial specific expression of we of JAM-2 expression on cell or on endothelial cells from results with the different of the described in Endothelial cell and expressed low of JAM-2 on the cell surface and variable of JAM-1 We to JAM-2 on epithelial cell whereas the of expressed JAM-1 with similar to the cell This is with the expression of JAM-1 by epithelial cells as (8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar), and the expression of JAM-2 to and in lymphoid organs or vascular structures of the kidney. of endothelial cells was of Peyer's lymph and Endothelial cells identified by their with both and J. Cell Biol. 99: PubMed Scopus Google Scholar). The cell was for JAM-1 or JAM-2 and the results are shown in B. kidney and Peyer's cells that for and expressed JAM-2 or JAM-1, in organs, endothelial cells express JAM-2 and JAM-1 in the was on cells from lymph JAM-2 and JAM-1 expression and found on a of cells, reflecting a heterogeneity of endothelial cell within Taken together, the results of and show that JAM-2 expression is to of endothelial cells found in Peyer's and lymph the cell from high endothelial venules expressed the of JAM-2, we cell to further the localization of JAM-2, and with that of JAM-1. The localization of the JAM-2 protein on the surface of the endothelial cells was to cell-cell contacts The for JAM-2 was than that for JAM-1 and in the cells. we to JAM-2 present cell-cell contacts with JAM-2 or with molecule on the we the JAM-2 protein to green fluorescent protein and transfected the into cells. cells transfected with JAM-2 was in cell-cell contacts two cells, both cells expressed the protein The contacts and cells of JAM-2 by The was cells transfected with the molecule This that JAM-2 or JAM-1 to be localized cell-cell with cells transfected with both that JAM-1 was to with JAM-2 a of JAM-2, we with we to the of and the molecular of JAM-2 of cells transfected with encoding the sequence of shown in the a of from of transfected cells and was of cells of the with we a of the molecular from to the from a with the This was in with the molecular of the JAM-2 on cell the molecular of for JAM-2 protein was and JAM-1 protein was as a of molecular This in JAM-1 and JAM-2 was further by of the proteins surface of transfected cells. shown in of and for and This was has a molecular of To the by which JAM-2 was specifically localized to cell-cell video was cells, transfected with the fluorescent molecule, and into for cell surface expression of was was cell-cell contacts cells the of cell-cell localization of to cell junctions was and was detected the novel contact the cells the cell-cell contact The protein was in the cells, to the or Interestingly, the localization of JAM-2 the cell-cell contacts was during the of the contact cell This was specifically localized to the cell localization was To further the for JAM-2 video was the cell monolayer the JAM-2 their contact JAM-2 localization the indicating that JAM-2 was to a of cells the to into the Interestingly, cells contacts with cells that results the that JAM-2 may play a role in the or of cell-cell a of molecules participating in cell-cell contacts been shown to regulate the paracellular permeability of cell we JAM-2 of reduced the paracellular permeability to and sealing of cell by whereas of the molecule receptor the paracellular permeability The of reduced the paracellular permeability of the cells monolayer as described for JAM-1 (8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar). cells present tight and paracellular permeability has been shown to be regulated by molecules participating in tight and we to the of JAM-2 to junctional complexes. To we transfected the protein in cells, known to possess tight and shown in for and with occludin was specifically in cell-cell contacts the of the tight and to the the we of due to the of the The localization of to tight junctions was more and with was whereas was found in the junctions with antibody results JAM-2 was transfected indicating that JAM-2 localization to tight results that JAM-2 the of a novel junctional adhesion molecule, to tight of to tight cells, transfected with with and of from to are shown for or occludin The on was as the the tight junctional on and and to composition from of and are shown The for are by a and with or are in whereas of is shown in The of tight and junctions are by and We the and of JAM-2, a novel junctional adhesion molecule of endothelial cells. adult JAM-2 expression is to cells, endothelial cells in the and of lymphoid The identification of JAM-2 is by a selective of RNA which to transcripts of The sequence of the in is on the sequence participating to the of immunoglobulin JAM-2 is a protein with two Ig and The molecule is to the recently described JAM-1 (7Malergue F. Galland F. Martin F. Mansuelle P. Aurrand-Lions M. Naquet P. Mol. Immunol. 1998; 35: 1111-1119Crossref PubMed Scopus (87) Google Scholar, 8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar). domains, JAM-2 two more than JAM-1, which to that is as a JAM-1, which was as a molecule (8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar, I. A. Courtet M. K. Pasquier L. Eur. J. Immunol. 1998; PubMed Google Scholar). of sequence JAM-1 and JAM-2 are identified within their the of JAM-1 was recently shown to and be to may the specific localization of both molecules to the tight junctions of polarized cells K. D. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, F. M. S. Dejana E. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The specific localization of the in which the sequence was a role for sequence in the of the proteins K. D. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the protein sequence identified as for may be to JAM-2 to cell-cell a role for in the of cell-cell contacts was recently suggested S. C. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. T. Y. S. Y. Fujimoto T. Y. S. J. Cell Biol. 1998; PubMed Scopus Google Scholar). we a role of the domains in the specific localization of the proteins JAM-2 and JAM-1 in the contacts transfected cells. The of JAM-2 localization to cell-cell contacts was JAM-2 protein to green fluorescent protein and video of during the of cell-cell contacts that the protein was within minutes to the contacts cells. cell-cell contacts the JAM-2 in a indicating that JAM-2 is in the of cell and may play a role in cell-cell contact organization. The further from paracellular permeability in cells transfected with or similar reduced paracellular permeability was described of and JAM-1, two molecules participating in and tight (8Martin-Padura I. Lostaglio S. Schneemann M. Williams L. Romano M. Fruscella P. Panzeri C. Stoppacciaro A. Ruco L. Villa A. Simmons D. Dejana E. J. Cell Biol. 1998; 142: 117-127Crossref PubMed Scopus (1158) Google Scholar, M. M. K. M. I. Stoppacciaro A. Ruco L. Dejana E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). Accordingly, expressed in cells, JAM-2 was with and occludin, two of tight junctions M. Hirase T. Itoh M. Nagafuchi A. Yonemura S. Tsukita S. 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