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First published online December 1, 2003
doi: 10.1242/10.1242/jcs.00930

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Junctional adhesion molecules (JAMs): more molecules with dual functions?

¹ Institute of Cell Biology, ZMBE, University of Münster, 48149 Münster, Germany
² Max-Planck-Institute of Vascular Biology, 48149 Münster, Germany
³ Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan

View larger version (24K): [in a new window]   Fig. 1. Ig-SF proteins at TJs. (A) All Ig-SF proteins present at TJs belong to the CD2 subfamily with a membrane-distal V-type Ig-domain and a membrane-proximal C2-type Ig-domain. Putative N-linked glycosylation sites are illustrated by dots. Disulfide bridges and putative additional intramolecular disulfide bridges formed by conserved cysteine residues in the C2-type Ig-domain are indicated. The sizes of the cytoplasmic domains (mouse molecules) are indicated at the bottom of each molecule. TJ localization has so far been shown for JAM-A, JAM-C, CAR, ESAM and JAM4 (see text for details). (B) A phylogenetic tree (Clustal W program, residue weight table PAM250; human CD2 is used as an outgroup) indicates that JAM-A, JAM-B and JAM-C, as well as CAR, ESAM and JAM4, form individual subfamilies. (C) All six Ig-SF molecules end in canonical PDZ domain binding motifs, which are of type II for JAM-A, JAM-B and JAM-C, and type I for CAR, ESAM and JAM4. The subcellular localization of two proteins with a similar structural organization, BT-IgSF (Suzu et al., 2002) and JAML (Moog-Lutz et al., 2003), has not yet been addressed; these molecules are not included in this figure. P, position of the amino acids with respect to the C-terminal aa, which is designated P0; , hydrophobic residue; X, any residue.

View larger version (18K): [in a new window]   Fig. 2. The role of JAM-A, JAM-B and JAM-C in leukocyte-plateletendothelial cell interactions. Homophilic and heterophilic interactions of JAM-A, JAM-B and JAM-C suggest that various heterotypic cell-cell interactions might be supported by JAMs. Binding of leukocytes to endothelial cells might be supported by integrins LFA-1 and 4ß1 binding to JAM-A and JAM B, respectively, on endothelial cells. Note that the 4ß1-mediated association with JAM-B seems to be enhanced by JAM-C co-expression with 4ß1 on the same leukocyte. Leukocyte binding to endothelial cells might also be mediated by leukocyte JAM-C binding to endothelial JAM-B. Leukocyte adherence to platelet deposits is mediated by the leukocyte integrin Mac-1 binding to JAM-C on platelets. Platelet binding to endothelial cells might be supported by JAM-A homophilic interactions. The associations illustrated in this figure have been shown in different experimental systems. Static cell-substrate adhesion assays with recombinant proteins immobilized on plastic were used to show the interaction between JAM-C and JAM-B (Arrate et al., 2001; Liang et al., 2002), 4ß1 and JAM-B (Cunningham et al., 2002), Mac-1 and JAM-C (Santoso et al., 2002), and JAM-A and JAM-A (Babinska et al., 2002a). Static cell-cell adhesion assays showed the association between LFA-1 and JAM-A (Ostermann et al., 2002), Mac-1 and JAM-C (Santoso et al., 2002) and between JAM-A and JAM-A (Babinska et al., 2002a). An interaction in cell-cell adhesion assays under flow conditions has so far been shown for LFA-1 and JAM-A (Ostermann et al., 2002), as well as for Mac-1 and JAM-C (Santoso et al., 2002).

View larger version (23K): [in a new window]   Fig. 6. Multiprotein-complexes at TJs. Three major multiprotein complexes are located at TJs. The ZO-1-ZO-2-ZO-3 complex is associated with occludin, claudins and JAMs through multiple interactions. ZO-1 directly associates with all three integral membrane proteins at TJs, i.e. occludin, claudins and JAMs. ZO-2 and ZO-3 directly associate with ZO-1. Both ZO-2 and ZO-3 can also be directly targeted to the plasma membrane by a direct association with occludin and claudins. The PAR-3-aPKC-PAR-6 complex is targeted to the plasma membrane through the interaction of PAR-3 with JAMs. The active form of Cdc42 can associate with the complex by binding to PAR-6, leading to the activation of aPKC. The Pals1-PATJ complex is associated with the membrane through Pals1 binding to CRB1 and CRB3. PATJ associates with Pals1 through its N-terminal MAGUK recruitment (MRE) domain that binds to the L27N domain of Pals1. It also associates with ZO-3 and claudin-1 through PDZ domains. CRB1 and CRB3, similar to the Drosophila orthologue Crumbs, are both localized at the apical surface of epithelial cells but are concentrated at TJs. These three protein complexes might exist independently, but they could also be physically linked. For instance, the Pals1-PATJ complex could be linked to the ZO-1-ZO-2-ZO-3-complex through PATJ binding to ZO-3. In addition, Pals-1 can directly associate with PAR-6 providing a link between the Pals1-PATJ and the PAR-3-aPKC-PAR-6 complexes. Genetic evidence from studies in Drosophila suggests that these protein complexes are also functionally linked in the regulation of epithelial cell polarization (Tanentzapf and Tepass, 2003; Bilder et al., 2003).

View larger version (21K): [in a new window]   Fig. 4. The PAR-3-aPKC-PAR-6 complex is associated with JAMs through PAR-3. PAR-3 binds directly to JAM-A, JAM-B and JAM-C through its first PDZ domain. Atypical PKC (aPKC) links PAR-3 with PAR-6. The binding of active Cdc42 to the CRIB domain of PAR-6 results in aPKC activation, possibly through a Cdc42-induced conformational change of PAR-6. A direct association between PAR-3 and PAR-6 in vitro, mediated through the PDZ domain 1 of PAR-3 and the PDZ domain of PAR-6, has also been reported (Lin et al., 2000).

View larger version (17K): [in a new window]   Fig. 3. PDZ-domain-containing proteins at TJs associated with JAMs. Four TJ-associated peripheral membrane proteins, ZO-1, AF-6, PAR-3 and MUPP1, directly bind to JAM-A. ZO-1 and PAR-3 associate also with JAM-B and JAM-C. In all cases, the associations are mediated through PDZ-domain-dependent interactions. Note that the PDZ domain(s) of ZO-1 interacting with JAM-B and JAM-C have not yet been determined.

View larger version (22K): [in a new window]   Fig. 5. Stages of cell-cell contact formation. (A) Migrating cells without cell contact protrude lamellipodia and filopodia at the leading edge of the cell. (B) Initial cell contacts at the tips of thin cellular protrusions result in the formation of primordial, spot-like adherens junctions or puncta, which are positive for E-cadherin, ZO-1 and JAM-A. (C) On further maturation of cell-cell contacts, the spot-like junctions fuse into a linear pattern; the cells start to polarize and proteins specifically enriched at adherens junctions (E-cadherin) or TJs (ZO-1, JAM A) start to segregate; (D) In fully polarized cells, proteins specific for AJs and TJs are completely segregated, and adherens junctions and TJs can be distinguished at a structural level. The figure is based on previous studies (Yonemura et al., 1995; Adams et al., 1996; Ando-Akatsuka et al., 1999).

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