PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase.
Platelet-derived growth factor receptor (PDGF-R) phosphorylation at tyrosines 740/751 and insulin receptor phosphorylation of insulin receptor substrate-1 effects the recruitment and activation of phosphatidylinositol-3-OH kinase (PI(3)K). Changes in PI(3)K activity correlate with cell growth but its downstream signal transducers are unknown. Activation of the 70/85K S6 kinases (pp70S6k) by serine phosphorylation results in 40S ribosomal protein S6 phosphorylation and is important for G1 cell-cycle transition in a variety of cells. Although receptor tyrosine kinases activate the microtubule-associated protein kinase cascade through SH2-/SH3-adaptor proteins, Sos and c-Ras, it is unclear how tyrosine kinases are coupled to the pp70S6k phosphorylation cascade. Here we report that PI(3)K mediates PDGF or insulin receptor signalling to pp70S6k. PI(3)K-mediated activation of pp70S6k is independent of conventional protein kinase C isoforms. Additionally, rapamycin blocks pp70S6k activation by all mitogens, without inhibiting PI(3)K, and acts downstream in this signalling system.
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
J
J
Chung
T C
TC
Grammer
K P
KP
Lemon
A
A
Kazlauskas
J
J
Blenis
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D007328:Insulin / Q000378:metabolism; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D020123:Sirolimus; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D010982:Platelet-Derived Growth Factor; D011090:Polyenes; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011972:Receptor, Insulin; D017479:Receptors, Platelet-Derived Growth Factor; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D010738:Type C Phospholipases; D000077191:Wortmannin