A Ras Signaling Complex Controls the RasC-TORC2 Pathway and Directed Cell Migration

SummaryRas was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway. In addition, PKB and PKB-related PKBR1 phosphorylate Sca1 and regulate the membrane localization of the Sca1/RasGEF/PP2A complex, and thereby RasC activity, in a negative feedback fashion. Thus, our study uncovered a molecular mechanism whereby RasC activity and the spatiotemporal activation of TORC2 are tightly controlled at the leading edge of chemotaxing cells.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (299 K)Download as PowerPoint slideHighlights► A Ras chemotactic signaling complex: a scaffold (Sca1), two RasGEFs, and PP2A ► The Sca1 complex regulates cell motility and signal relay via adenylyl cyclase ► The Sca1 complex controls the RasC-TORC2-PKB pathway at the leading edge ► TORC2 and PKB control the Sca1 complex and RasC through negative feedback