ABSTRACT
Th rough their cytoplasmic tails, JAMs directly interact with various cytoplasmic proteins. All these proteins contain one or several PDZ domains, a domain consisting of 80 to 90 AA that is used to mediate protein-protein interactions. PDZ domain-containing proteins, in particular those containing multiple PDZ domains, are frequently used to assemble multiprotein complexes at the membrane. JAM-A, -B and -C all contain a conserved motif that mediates the interaction with PDZ domains, and the interactions with the hitherto known direct binding partners, i.e., AF-6/afadin, ZO-1, Par-3 and MUPP1, are mediated through this motif and a PDZ domain of the binding partner (Fig. 5) (Ebnet et al. 2004). Th e fi rst clear evidence for a role of JAMs in the organization of cell-cell contacts came with the identifi cation of the cell polarity protein Par-3 as direct binding partner for JAM-A (Ebnet et al. 2001). Par-3 forms a complex with Par-6 and atypical PKC (aPKC) that localizes to the tight junction (TJ). Th e TJs represent a specifi c structure at the most apical region of the lateral cell-cell contact that is implicated in the regulation of paracellular permeability but also in the separation of the apical from the basolateral membrane domain (Tsukita et al. 2001). A critical role for the Par-aPKC complex for the formation of functional TJs is suggested by the observations that overexpression of dominant-negative mutants or siRNA-mediated downregulation of individual components of the complex
disturb or retard TJ formation in cultured epithelial cells. Th e function of JAM-A in TJ formation thus most likely resides in targeting the Par-aPKC complex to sites of cell-cell contacts where it is required to establish specifi c membrane domains. Th is role of JAM-A might be of particular importance during cell-cell contact formation. In the absence of cell-cell adhesion, for example, during migration, cells form thin protrusions to scan the extracellular environment. Th e protrusions are dynamic in the absence of cell-cell adhesion, and they are stabilized upon cell-cell contact formation (Adams et al. 1998). Signals mediated by the adhesion molecules regulate the further maturation of the cell-cell contacts. Interestingly, JAM-A is among the proteins that are present at the earliest sites of cell-cell adhesion during contact formation, the so-called primordial, spot-like junctions or puncta. Th e Par-aPKC complex is recruited shortly aft er the puncta are formed. Th us, a primary role of JAM-A might be to recruit the Par-aPKC complex and thereby regulate the correct localization of this complex, which regulates the further cell contact formation that eventually leads to fully matured lateral cellcell contacts with TJs localized at the apex and separated from AJs. In accordance with this view, ectopic expression of a JAM-A mutant that cannot bind Par-3 leads to defects in the formation of functional TJs and in the development of apico-basal polarity (Rehder et al. 2006). Interestingly, a similar function albeit in a diff erent cell type seems to be true for JAM-C as well as revealed in JAM-C knockout mice. Th e inactivation of the JAM-C gene in mice leads to male sterility (Gliki et al. 2004), and the reason for the sterility turned out to be a blockade in the development of spermatids. During normal spermatogenesis, spermatids undergo intimate contacts with Sertoli cells, and this interaction in part is mediated by JAM-C and JAM-B expressed by spermatids and Sertoli cells, respectively. Cell polarity proteins such as Par-6, aPKC and Cdc42 are localized in close proximity of the site of spermatid-Sertoli cell interaction. Th is polarized localization is lost in JAM-C knockout spermatids, resulting in a blockade of spermatid polarization and ultimately in sterility (Gliki et al. 2004). Th us, JAM-C expressed by spermatids provides another example of the functional role of JAMs: through homophilic and heterophilic interactions, JAMs are localized to specifi c subcellular sites, and through their cytoplasmic domains, they recruit their binding partners to the specifi c localizations where these are required to regulate developmental processes. A recent report describes the localization of JAM-C at autotypic junctions of Schwann cells in myelinated nerves (Scheiermann et al. 2007). Schwann cells wrap around the axons to allow for saltatory conduction. At specifi c sites such as the paranodal loops and Schmidt-Lanterman incisures, the Schwann cells form tight interactions between membrane patches of the same cell, and these tight interactions are necessary for effi cient electrical insulation. In the absence of JAM-C, the integrity of the myelin sheath is altered and nerve conduction is defective. It is not clear yet whether this defects results from a lack of adhesive
interactions, from a lack of a specifi c membrane domain required to establish these tight interactions or from both. Nevertheless, this example adds another facet to the versatility of JAMs.
