Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex

• Published in: The Journal of cell biology 2012-08, Vol.198 (4), p.677-693
• Main Authors: Elbediwy, Ahmed, Zihni, Ceniz, Terry, Stephen J, Clark, Peter, Matter, Karl, Balda, Maria S
• Format: Article
• Language: English
• Subjects: Actin Capping Proteins - physiology; Adaptor Proteins, Signal Transducing - metabolism; Caco-2 Cells; cdc42 GTP-Binding Protein - metabolism; Cell adhesion & migration; Cell Adhesion - physiology; Cellular biology; Cytoskeletal Proteins - metabolism; Cytoskeleton; Epithelial Cells - cytology; Epithelial Cells - metabolism; Female; GTPase-Activating Proteins - biosynthesis; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; GTPase-Activating Proteins - physiology; Humans; Intercellular Junctions - metabolism; Intercellular Junctions - physiology; Multiprotein Complexes - physiology; RNA, Small Interfering - genetics; RNA-protein interactions; Signal transduction; Signal Transduction - physiology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201202094

Epithelial cell-cell adhesion and morphogenesis require dynamic control of actin-driven membrane remodeling. The Rho guanosine triphosphatase (GTPase) Cdc42 regulates sequential molecular processes during cell-cell junction formation; hence, mechanisms must exist that inactivate Cdc42 in a temporally and spatially controlled manner. In this paper, we identify SH3BP1, a GTPase-activating protein for Cdc42 and Rac, as a regulator of junction assembly and epithelial morphogenesis using a functional small interfering ribonucleic acid screen. Depletion of SH3BP1 resulted in loss of spatial control of Cdc42 activity, stalled membrane remodeling, and enhanced growth of filopodia. SH3BP1 formed a complex with JACOP/paracingulin, a junctional adaptor, and CD2AP, a scaffolding protein; both were required for normal Cdc42 signaling and junction formation. The filamentous actin-capping protein CapZ also associated with the SH3BP1 complex and was required for control of actin remodeling. Epithelial junction formation and morphogenesis thus require a dual activity complex, containing SH3BP1 and CapZ, that is recruited to sites of active membrane remodeling to guide Cdc42 signaling and cytoskeletal dynamics.