PDGF-DEPENDENT AND INSULIN-DEPENDENT PP70(S6K) 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)(1-5). Changes in PI(3)K activity correlate with cell growth but its downstream signal transducers are unknown(4,5). Activation of the 70/85K S6 kinases (pp70(S6k)) by serine phosphorylation(6,7) results in 40S ribosomal protein S6 phosphorylation and is important for G1 cell-cycle transition in a variety of cells(8-11). Although receptor tyrosine kinases activate the microtubule-associated protein kinase cascade through SH2-/SH3-adaptor proteins, Sos and c-Ras(12), it is unclear how tyrosine kinases are coupled to the pp70(S6k) phosphorylation cascade. Here we report that PI(3)K mediates PDGF or insulin receptor signalling to pp70(S6k). PI(3)K-mediated activation of pp70(S6k) is independent of conventional protein kinase C isoforms. Additionally, rapamycin blocks pp70(S6k) activation by all mitogens(8-10), without inhibiting PI(3)M, and acts downstream this signalling system.