title: A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration.
abstract: Ras 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.
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0380, USA.
authors.forename: Pascale G
authors.initials: PG
authors.lastname: Charest
authors.forename: Zhouxin
authors.initials: Z
authors.lastname: Shen
authors.forename: Ashley
authors.initials: A
authors.lastname: Lakoduk
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.forename: Steven P
authors.initials: SP
authors.lastname: Briggs
authors.forename: Richard A
authors.initials: RA
authors.lastname: Firtel
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D004023:Dictyostelium / Q000502:physiology; D017353:Gene Deletion; D006801:Humans; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015800:Protozoan Proteins / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D020663:ras Guanine Nucleotide Exchange Factors / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C493245:CRTC2 protein, human; D015800:Protozoan Proteins; D014157:Transcription Factors; C104358:aimless protein, Dictyostelium; D020663:ras Guanine Nucleotide Exchange Factors; D000242:Cyclic AMP; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins