PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase

Nature. 1994 Jul 7;370(6484):71-5. doi: 10.1038/370071a0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Androstadienes / pharmacology
  • Animals
  • Cell Line
  • Enzyme Activation
  • Insulin / metabolism
  • Mice
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Platelet-Derived Growth Factor / metabolism*
  • Polyenes / pharmacology
  • Protein Kinase C / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor, Insulin / metabolism
  • Receptors, Platelet-Derived Growth Factor / genetics
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Sirolimus
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism
  • Wortmannin

Substances

  • Androstadienes
  • Insulin
  • Platelet-Derived Growth Factor
  • Polyenes
  • Phosphotransferases (Alcohol Group Acceptor)
  • Receptor, Insulin
  • Receptors, Platelet-Derived Growth Factor
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Protein Kinase C
  • Type C Phospholipases
  • Sirolimus
  • Wortmannin