A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration.
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.
Charest
Pascale G
PG
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0380, USA.
Shen
Zhouxin
Z
Lakoduk
Ashley
A
Sasaki
Atsuo T
AT
Briggs
Steven P
SP
Firtel
Richard A
RA
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*
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