Review the Role of Junctional Adhesion Molecules in Cell-Cell
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Histol Histopathol (2005) 20: 197-203 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review The role of junctional adhesion molecules in cell-cell interactions T. Keiper1, S. Santoso2, P.P. Nawroth1, V. Orlova1 and T. Chavakis1 1Department of Internal Medicine I, University Heidelberg, Heidelberg and 2Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University, Giessen, Germany Summary. Cell-cell-interactions are important for the intracellularly to cytoskelettal signaling molecules such regulation of tissue integrity, the generation of barriers as zonula occludens-1 (ZO-1) or cingulin. (ii) Adherens between different tissues and body compartments junctions (zonula adherens) formed by cadherins, i.e. thereby providing an effective defence against toxic or transmembrane glycoproteins that promote calcium- pathogenic agents, as well as for the regulation of dependent, homophilic cell-cell contacts. The link inflammatory cell recruitment. Intercellular interactions between cell-membrane-associated cadherins and the are regulated by adhesion receptors on adjacent cells actin cytoskeleton is mediated by intracellular catenins. which upon extracellular ligand binding mediate VE-cadherin is a member of this family specifically intracellular signals. In the vasculature, neighbouring found in the inter-endothelial junctions. (iii) Gap endothelial cells interact with each other through various junctions are clusters of transmembrane hydrophilic adhesion molecules leading to the generation of channels that do not serve a cellular contact function, but junctional complexes like tight junctions (TJs) and promote the exchange of ions and small molecules adherens junctions (AJs) which regulate both leukocyte relevant for lateral transmission of molecular endothelial interactions and paracellular permeability. In information. Here, we will focus on the family of JAMs, this context, emerging evidence points to the importance which are components of the tight junctions. of the family of junctional adhesion molecules (JAMs), which are localized in tight junctions of endothelial and Structure and cellular expression of JAMs epithelial cells and are implicated in the regulation of both leukocyte extravasation as well as junction JAMs belong to the CD2 subgroup of the formation and permeability. immunoglobulin superfamily, consisting of two extracellular Ig-like domains, a membrane-distal V-Ig- Key words: Junctions, JAM, Cell adhesion, Leukocyte domain and a membrane-proximal C2-Ιg-domain transmigration, Inflammation, Permeability (Williams and Barclay, 1988; Barclay et al., 1997), followed by a single transmembrane region and a short cytoplasmic tail. Table 1 shows a synopsis of JAMs. The Interendothelial junctions genes for JAM-A, JAM-B and JAM-C are localized on different chromosomes and the encoded mature Depending on the tissue/organ location of a glycoproteins have molecular masses of 30-43 kDa particular vascular bed, endothelial cells possess a (Bazzoni, 2003; Chavakis et al., 2003). At their final number of junctions that maintain vascular integrity and carboxy-terminus (5 C-terminal amino acids) all three regulate permeability and leukocyte transmigration. At molecules have a class-II PDZ domain-binding motif, least three types of junctions have been described which predisposes them to interact with PDZ-domain- (Kemler, 1993; Dejana et al., 1995, 2001; Johnson-Leger containing molecules, such as the ones found in tight et al., 2000): (i) Tight junctions (zonula occludens), the junctions (Ebnet et al., 2004). The recently described most apical junctions, which form a very close JAM-4 differs from the three members of the JAM intercellular adhesive contact and which include three subfamily in its cytoplasmic tail. As opposed to 40-49 types of transmembrane proteins, occludin, claudins and residues of other JAMs, the cytoplasmic domain of junctional adhesion molecules (JAMs), which are linked JAM-4 consists of 105 residues and its 5 C-terminal residues represent a type-I PDZ domain-binding motif Offprint requests to: Dr. T. Chavakis, Department of Internal Medicine I, (Hirabayashi et al., 2003). JAM-A, also referred to as University Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, JAM-1 or F11R (Kornecki et al., 1990; Naik et al., 1995; Germany. e-mail: [email protected] Sobocka et al., 2000) is found on different circulating 198 JAMs and cell adhesion blood cells including platelets, monocytes, lymphocytes This dimerization process seems to be a preceding step and erythrocytes as well as on endothelial and epithelial and structural prerequisite for homophilic interaction in cells. The expression pattern of JAM-B (also called VE- trans (Kostrewa et al., 2001). In contrast, such JAM, human JAM-2, mouse JAM-3), which shares a homophilic interactions have not been described for 35% sequence identity with JAM-A is more restricted, JAM-B and JAM-C yet. Our preliminary observations as it localizes on vascular and lymphatic endothelium indicate that such a potential interaction exists for JAM- and especially at high endothelial venules, suggesting a C as well (Orlova et al., unpublished observations). special role for JAM-B in lymphocyte homing (Palmeri However, as the dimerization motif is also present in et al., 2000). JAM-C (also referred to as human JAM-3 JAM-B (RLE) and JAM-C (RIE), dimer formation is and mouse JAM-2) is expressed on endothelial cells, on probable for JAM-B and JAM-C. Moreover, this platelets (Aurrand-Lions et al., 2001a,b; Santoso et al., common dimerization motif allows potential interactions 2002) and on epithelial cells (Chavakis et al., amongst the different members of the JAM family or unpublished observation). Moreover, human JAM-C is dimers thereof to be envisioned. In fact, JAM-B has found on T-cells and natural killer cells (Liang et al., been shown to interact with JAM-C (Liang et al., 2002), 2002; Santoso et al., 2002). Contrastingly, mouse T- and although the structural requirements of this interaction NK-cells do not seem to express JAM-C (Johnson-Leger remain to be elucidated. et al., 2002). The homophilic interaction of JAM-A probably affects tight-junction formation, stability, and Homophilic and heterophilic interactions of JAMs paracellular permeability, as inhibition of JAM-A with either blocking antibodies or soluble recombinant JAM- Homophilic interactions: Implications for tight junction A protein resulted in a significant delay of the recovery formation and regulation of paracellular permeability of transepithelial electrical resistance in epithelial cells (Liang et al., 2000; Liu et al., 2000). Homophilic The first evidence that JAMs could undergo a interactions between JAM family members might also homophilic binding with JAM molecules came from contribute to cell-cell adhesion either in a homotypic transfection studies. In JAM-A-, -B, or –C-transfected (e.g. between adjacent endothelial cells) and/or a cells the JAM molecules could be found at sites where heterotypic manner (e.g. between leukocytes, endothelial transfected cells faced other transfected cells but not at cells, or platelets). However this has to be addressed in sites where transfected cells contacted non-transfected detail in future studies. cells (Martin-Padura et al., 1998; Cunningham et al., Ectopic expression of JAM-A or JAM-C in 2000; Aurrand-Lions et al., 2001a,b; Ebnet et al., 2001, polarized epithelial cells results in their co-distribution 2003). At least for JAM-A such an interaction has also with the TJ-marker protein ZO-1 suggesting direct been shown biochemically. Soluble recombinant association of both JAM molecules with TJs (Aurrand- extracellular murine JAM-A interacts with itself, and in Lions et al., 2001a). The subcellular localization of particular, extracellular soluble homodimers of JAM-A JAM-B is less clear because with ectopic expression in bind non-covalently to immobilized JAM-A MDCK epithelial cells it is not specifically enriched at homodimers (Bazzoni et al., 2000a). This homophilic TJs (Aurrand-Lions et al., 2001b). A direct interaction interaction was prevented by monoclonal antibody with several PDZ-domain-containing molecules at tight against JAM-A, which recognizes dimeric rather than junctions has been particularly shown for JAM-A: Such monomeric structures (Arrate et al., 2001). The N- PDZ-domain molecules include ZO-1 (Bazzoni et al., terminal membrane-distal V-type Ig-like domain of 2000b), AF6/afadin (Yamamoto et al., 1997; Ebnet et al., JAM-A plays an important role in homophilic 2000), MUPP 1 (multi-PDZ-domain-protein 1) interactions of JAM-A (Babinska et al., 2002). Crystal (Hamazaki et al., 2002), and PAR-3 (partitioning structure analysis showed that JAM-A forms U-shaped defective), which forms a complex with atypical protein homodimers in cis through a dimerization motif (RVE), kinase C and PAR-6 (Ebnet et al., 2001; Joberty et al., which resides in the VH fold (Kostrewa et al., 2001). 2000; Johansson et al., 2000; Lin et al., 2000; Qiu et al., Table 1. The JAM family members and their molecular mass, chromosomal localization and their homology to the murine protein. JAMs end in a type-II PDZ-domain-binding motif. X: position of the amino acids with respect to X0, which indicates the C-terminal amino acid. PROTEIN MOLECULAR MASS CHROMOSOMAL HOMOLOGY TO PDZ-DOMAIN- (kDa) LOCALIZATION MURINE PROTEIN BINDING MOTIFS X-4 X-3 X-2 X-1 X0 JAM-A 32 1 67% S S F L V JAM-B 40 21 79% K S F I I JAM-C 43 11 86% S S F V I 199 JAMs and cell adhesion 2000; Suzuki et al., 2001). In the case of JAM-C, its heterophilic interaction in trans between JAM-B and association with ZO-1 is dependent on the JAM-C (Arrate et al., 2001; Liang et al., 2002), several phosphorylation status of the molecule, in particular, the lines of evidence point to the fact that JAMs are also interaction of JAM-C with ZO-1 is reciprocally engaged as counter-receptors for leukocyte integrins: In dependent on the phosphorylation of the Ser281 in JAM- particular, JAM-A binds the leukocyte integrin αLß2 C (Ebnet et al., 2003).