SH3BP1, an Exocyst-Associated RhoGAP, Inactivates Rac1 at the Front to Drive Cell Motility

• Published in: Molecular cell Vol. 42; no. 5; pp. 650 - 661
• Main Authors: Parrini, Maria Carla, Sadou-Dubourgnoux, Amel, Aoki, Kazuhiro, Kunida, Katsuyuki, Biondini, Marco, Hatzoglou, Anastassia, Poullet, Patrick, Formstecher, Etienne, Yeaman, Charles, Matsuda, Michiyuki, Rossé, Carine, Camonis, Jacques
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2011
• Subjects: Animals; biosensors; cell movement; Cell Movement - physiology; Down-Regulation; Enzyme Activation; Gene Silencing; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; GTPase-Activating Proteins - physiology; Microtubule-Organizing Center - physiology; Microtubule-Organizing Center - ultrastructure; motility; phenotype; proteins; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; ral GTP-Binding Proteins - genetics; ral GTP-Binding Proteins - physiology; Rats; signal transduction; Transcription Factors - metabolism; Transcription Factors - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.03.032

The coordination of the several pathways involved in cell motility is poorly understood. Here, we identify SH3BP1, belonging to the RhoGAP family, as a partner of the exocyst complex and establish a physical and functional link between two motility-driving pathways, the Ral/exocyst and Rac signaling pathways. We show that SH3BP1 localizes together with the exocyst to the leading edge of motile cells and that SH3BP1 regulates cell migration via its GAP activity upon Rac1. SH3BP1 loss of function induces abnormally high Rac1 activity at the front, as visualized by in vivo biosensors, and disorganized and instable protrusions, as revealed by cell morphodynamics analysis. Consistently, constitutively active Rac1 mimics the phenotype of SH3BP1 depletion: slow migration and aberrant cell morphodynamics. Our finding that SH3BP1 downregulates Rac1 at the motile-cell front indicates that Rac1 inactivation in this location, as well as its activation by GEF proteins, is a fundamental requirement for cell motility. [Display omitted] ► The RhoGAP SH3BP1 interacts and colocalizes with the exocyst in motile cells ► SH3BP1 is required for cell migration because it inactivates Rac1-GTP at the front ► GDP/GTP cycling of Rac1 is needed to generate stable and organized protrusions ► SH3BP1 connects two motility-driving pathways: the Ral/exocyst and Rac pathways