Control of cell adhesion dynamics by Rap1 signaling

Abstract

Individual cells in their particular environments adhere to the extracellular matrix (ECM) and their neighbours via integrin-containing and cadherin-containing complexes, respectively. The dynamics of these interactions regulate the formation and maintenance of complex tissues. An expanding body of evidence accentuates the role of the small Rap1 GTPase and its associated signaling network in many of these processes. In this review we will discuss more recently revealed roles of Rap1 signaling by primarily focusing on functions of the Rap1 effectors RIAM, KRIT-1/CCM1 and AF-6/Afadin in junctional regulation of the vascular system and in epithelial cells. Furthermore, we will describe novel findings on the Rap activator PDZ-GEF in the regulation of cell-cell adhesion between epithelial cells and within a stem cell niche.

Figure 1

(A) Rap1 is activated by a group of highly specific GEFs that perform a GDP/GTP nucleotide exchange reaction. Loaded with GTP, Rap1 is competent to associate with effector proteins to initiate downstream signaling. The RIAM, KRIT/CCM1 and AF-6 protein are distinguished by various scaffolding domains: C, coiled-coil; P, proline-rich; RA, Ras associating; PH, Pleckstrin homology; ANK, Ankyrin repeat; FERM, band 4.1/Ezrin/Radixin/Moesin homology; FHA, fork head associated; DIL, dilute/Myo5 homology and PDZ, PSD-95/Discs large/ZO-1 domains. (B) Schematic diagram of the RIAM and talin-dependent effect of Rap1 on integrin complexes and their increased affinity to ECM molecules. (C) Schematic view of the proteins that act downstream of Rap1 in endothelial junctions. All diagrams are incomplete depictions of Rap1-interacting proteins and complexes and restricted to the molecules referred to in the text.