Phosphoinositide-dependent protein kinase (PDK) activity regulates phosphatidylinositol 3,4,5-trisphosphate-dependent and -independent protein kinase B activation and chemotaxis.
Chemotactic cells must sense shallow extracellular gradients and produce localized intracellular responses. We previously showed that the temporal and spatial activation of two protein kinase B (PKB) homologues, PkbA and PkbR1, in Dictyostelium discoideum by phosphorylation of activation loops (ALs) and hydrophobic motifs had important roles in chemotaxis. We found that hydrophobic motif phosphorylation depended on regulation of TorC2 (target of rapamycin complex 2); however, the regulation of AL phosphorylation remains to be determined at a molecular level. Here, we show that two PDK (phosphoinositide-dependent protein kinase) homologues, PdkA and PdkB, function as the key AL kinases. Cells lacking both PdkA and PdkB are defective in PKB activation, chemotaxis, and fruiting body formation upon nutrient deprivation. The pleckstrin homology domain of PdkA is sufficient to localize it to the membrane, but transient activation of PdkA is independent of PIP(3) as well as TorC2 and dispensable for full function. These results confirm the importance of the TorC2-PDK-PKB pathway in chemotaxis and point to a novel mechanism of regulation of PDKs by chemoattractant.
Kamimura
Yoichiro
Y
Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Devreotes
Peter N
PN
D002633:Chemotaxis / Q000502:physiology*; D004023:Dictyostelium / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D048690:Fruiting Bodies, Fungal / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
D018129:Phosphatidylinositol Phosphates; D015800:Protozoan Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; C411869:PKBR-1 protein, Dictyostelium; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt