The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.
The serine/threonine protein kinase encoded by the Akt proto-oncogene is catalytically inactive in serum-starved primary and immortalized fibroblasts. Here we show that Akt and the Akt-related kinase AKT2 are activated by PDGF. The activation was rapid and specific, and it was abrogated by mutations in the Akt Pleckstrin homology (PH) domain. The Akt activation was also shown to depend on PDGFR beta tyrosines Y740 and Y751, which bind phosphatidylinositol 3-kinase (PI 3-kinase) upon phosphorylation. Moreover, Akt activation was blocked by the PI 3-kinase-specific inhibitor wortmannin and the dominant inhibitory N17Ras. Conversely, Akt activity was induced following the addition of phosphatidylinositol-3-phosphate to Akt immunoprecipitates from serum-starved cells in vitro. These results identify Akt as a novel target of PI 3-kinase and suggest that the Akt PH domain may be a mediator of PI 3-kinase signaling.
Franke
T F
TF
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Yang
S I
SI
Chan
T O
TO
Datta
K
K
Kazlauskas
A
A
Morrison
D K
DK
Kaplan
D R
DR
Tsichlis
P N
PN
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008954:Models, Biological; D015513:Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011519:Proto-Oncogenes; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000077191:Wortmannin; D018631:ras Proteins / Q000378:metabolism
D000730:Androstadienes; D004791:Enzyme Inhibitors; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017479:Receptors, Platelet-Derived Growth Factor; D000077191:Wortmannin; D018631:ras Proteins; C494920:Akt1 protein, rat; C494922:Akt2 protein, mouse; C494923:Akt2 protein, rat