Structural determinants of Junctional Adhesion Molecule A (JAM-A) function and mechanisms of intracellular signaling

Abstract

Junctional Adhesion Molecule A (JAM-A) is a multifunctional cell surface protein that has multiple evolutionarily conserved structural features. There is now conclusive evidence that discrete structural elements on JAM-A mediate intracellular signaling events that alter cell migration and paracellular permeability. Specifically, self-dimerization between extracellular Ig-like loops and close apposition of PDZ-dependent, JAM-A-associated intracellular scaffold proteins such as Afadin and guanine-nucleotide exchange factors mediate activation of Rap1 and modulation of epithelial cell migration by effects on beta1 integrin. While the same JAM-A structural features also modulate migration of other cell types and paracellular permeability in epithelia/endothelia, additional signaling proteins/mechanisms are probably involved. Recent insights into JAM-A outside-in signaling events that regulate these cellular functions are discussed.

Figure 1

A) Structure of JAM-A and general JAM-A signaling model. JAM-A (crystal structure in blue) has two extracellular Ig-like loops. The membrane distal domain, D1, is comprised of a variable immunoglobulin like loop (IgV) and mediates homodimerization through the motif colored in red. The membrane proximal domain, D2, is comprised of a constant immunoglobulin like loop (IgC). The cytoplasmic tail ends with a carboxy-terminal PDZ-binding motif (FLV) that binds to PDZ domain-containing scaffold proteins. Crystal structure information was reported by Prota et al. (21). The alpha helix depicted for the transmembrane domain is based on the protein sequence. Dimerization of JAM-A is mediated through binding interactions with D1 and brings into close apposition two PDZ-binding domains that facilitate the formation of PDZ containing scaffold protein complexes and subsequent signaling events. B) Model of outside-in signaling through JAM-A that regulates epithelial cell migration. In this model, dimerized JAM-A brings into close apposition Afadin/Rap1A and PDZGEF2 to activate Rap1A. The active GTPase acts to stabilize cell surface β1 integrin protein and regulate cell migration.

Figure 2

Mechanisms of JAM-A mediated leukocyte transmigration. Potential mechanisms for the effects of JAM-A (blue) on leukocyte (yellow) migration include: A) adhesion receptor-ligand interactions, B) alterations in endothelial/epithelial intracellular signaling due to trans-interactions with leukocytes, C) alterations in JAM-A leukocyte signaling and cell polarity through Par3/Par6/aPKC (green), and D) interference with JAM-A signaling by soluble JAM-A (sJAM-A, in blue). Not shown is intracellular leukocyte signaling due to trans-interactions as highlighted in 2B for endothelial/epithelial cells.