Vascular Endothelial Junction-associated Molecule, a Novel Member of the Immunoglobulin Superfamily, Is Localized to Intercellular Boundaries of Endothelial Cells

Abstract

During the process of lymphocyte homing to secondary lymphoid organs, such as lymph nodes and tonsils, lymphocytes interact with and cross a specialized microvasculature, known as high endothelial venules. There is a great deal of information available about the first steps in the homing cascade, but molecular understanding of lymphocyte transmigration through the intercellular junctions of high endothelial venules is lacking. In analyzing expressed sequence tags from a cDNA library prepared from human tonsillar high endothelial cells, we have identified a cDNA encoding a novel member of the immunoglobulin superfamily. The protein, which we have termed VE-JAM ("vascular endothelial junction-associated molecule"), contains two extracellular immunoglobulin-like domains, a transmembrane domain, and a relatively short cytoplasmic tail. VE-JAM is prominently expressed on high endothelial venules but is also present on the endothelia of other vessels. Strikingly, it is highly localized to the intercellular boundaries of high endothelial cells. VE-JAM is most homologous to a recently identified molecule known as Junctional Adhesion Molecule, which is concentrated at the intercellular boundaries of both epithelial and endothelial cells. Because the Junctional Adhesion Molecule has been strongly implicated in the processes of neutrophil and monocyte transendothelial migration, an analogous function of VE-JAM during lymphocyte homing is plausible.

Vascular Endothelial-Junctional Adhesion Molecule (VE-JAM)/JAM 2 Interacts with T, NK, and Dendritic Cells Through JAM 3

“…In normal fetal tissue, VE-JAM/JAM 2 is present in the vascular endothelium of small and large vessels, while in normal adult tissue, VE-JAM/JAM 2 is found in the endothelium of tonsillar and lymphatic HEV, as previously reported (1,2). We also identified VE-JAM/JAM 2 mRNA expression the spermatogenic cells of the epithelium in testicular seminiferous tubules, and in the intermediate trophoblasts of placenta for the first time.…”

“…In search of a molecule, we identified an endothelial-specific JAM homolog that proved to be the previously reported vascular endothelia-JAM (VE-JAM) (1) or JAM 2 (2), termed herein as VE-JAM/JAM 2. VE-JAM/JAM 2 is described in this work, as previously reported (1,2). It is expressed in a variety of fetal vascular endothelia, the HEV of the adult tonsil and lymph nodes.…”

Unique Structural Features That Influence Neutrophil Emigration Into the Lung

“…Most studies focus on the importance of interendothelial clefts as primary routes for neutrophil migration. Support for this notion stems from findings that PECAM-1 (CD31), junctional adhesion molecules (JAMs), VE-cadherin, and CD99 localize to interendothelial clefts and antibodies raised against these molecules can inhibit (anti-PECAM-1, anti-JAM-1, anti-CD99) or enhance (anti-VE-cadherin) leukocyte transendothelial migration (4,17,49,90,140,141,154,167,181,183,184,195,226). Although these studies suggest these molecules function as "gate keepers" regulating neutrophil transendothelial migration, specific studies addressing their role in neutrophil emigration in the lung are scarce.…”

Neutrophil transepithelial migration: role of toll-like receptors in mucosal inflammation

“…Interestingly, multiple members of the JAM protein family have also been shown to act as receptors for viruses (Bergelson et al 1997, Barton et al 2001 and have been shown to localize to intercellular junctions (Martin-Padura et al 1998, Liu et al 2000, Cohen et al 2001. The JAM proteins are type I transmembrane proteins consisting of an N-terminal signal peptide, an extracellular domain, a single membrane-spanning domain and a short cytoplasmic tail (Malergue et al 1998, MartinPadura et al 1998, Ozaki et al 1999, Williams et al 1999, Cunningham et al 2000, Liu et al 2000, Palmeri et al 2000, Sobocka et al 2000, Arrate et al 2001, Aurrand-Lions et al 2001a,b, Naik et al 2001, Liang et al 2002, Santoso et al 2002, Hirabayashi et al 2003, Moog-Lutz et al 2003. The extracellular domains of JAMs consist of two immunoglobulin-like loops, each containing an intradomain disulfide bond while the cytoplasmic tails of several members terminate in putative PDZ-binding motifs that appear to mediate binding to intercellular junction-associated scaffold proteins (Cunningham et al 2000, Ebnet et al 2000, 2001, Martinez-Estrada et al 2001, Hamazaki et al 2002, Santoso et al 2002, Hirabayashi et al 2003.…”