title: Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis.
abstract: In chemotactic cells, G protein-coupled receptors activate Ras proteins, but it is unclear how Ras-associated pathways link extracellular signaling to cell migration. We show that, in Dictyostelium discoideum, activated forms of RasC prolong the time course of TORC2 (target of rapamycin [Tor] complex 2)-mediated activation of a myristoylated protein kinase B (PKB; PKBR1) and the phosphorylation of PKB substrates, independently of phosphatidylinositol-(3,4,5)-trisphosphate. Paralleling these changes, the kinetics of chemoattractant-induced adenylyl cyclase activation and actin polymerization are extended, pseudopodial activity is increased and mislocalized, and chemotaxis is impaired. The effects of activated RasC are suppressed by deletion of the TORC2 subunit PiaA. In vitro RasC(Q62L)-dependent PKB phosphorylation can be rapidly initiated by the addition of a PiaA-associated immunocomplex to membranes of TORC2-deficient cells and blocked by TOR-specific inhibitor PP242. Furthermore, TORC2 binds specifically to the activated form of RasC. These results demonstrate that RasC is an upstream regulator of TORC2 and that the TORC2-PKB signaling mediates effects of activated Ras proteins on the cytoskeleton and cell migration.
authors.affiliation: Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Cai
authors.forename: Satarupa
authors.initials: S
authors.lastname: Das
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamimura
authors.forename: Yu
authors.initials: Y
authors.lastname: Long
authors.forename: Carole A
authors.initials: CA
authors.lastname: Parent
authors.forename: Peter N
authors.initials: PN
authors.lastname: Devreotes
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000502:physiology*; D004023:Dictyostelium / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D018631:ras Proteins; C109557:PiaA protein, Dictyostelium; C411869:PKBR-1 protein, Dictyostelium