title: Activation of p70/p85 S6 kinase by a pathway independent of p21ras.
abstract: The enzymes p70s6k and p85s6k are two isoforms of the same kinase and are important in mitogenesis. Both isoforms are activated by a complex phosphorylation event and lie on a common signalling pathway, distinct from that of the p42mapk/p44mapk kinases. Activation of p42mapk/p44mapk is triggered by sequential activation of the GDP-GTP exchange factor Sos, the GTP-binding protein p21ras, and protein kinases p74raf and p47mek (refs 7-10). As p21ras transformed cells have increased S6 phosphorylation, we tested whether the p70s6k/p85s6k signalling pathway bifurcates between p21ras and p42mapk/p44mapk. We found that mutants of p74raf and p21ras blocked activation of epitope-tagged p44mapk but not epitope-tagged p70s6k. Moreover, in cells expressing human platelet-derived growth factor receptors lacking the kinase-insert domain, the growth factor activates p21ras but not p70s6k/p85s6k. The critical autophosphorylation site for p70s6k/p85s6k activation within this domain is a tyrosine at residue 751. Our results show that the p70s6k/p85s6k signalling pathway is independent of p21ras, that it bifurcates from the p21ras pathway at the receptor, and that it is initiated by autophosphorylation at a specific site.
authors.affiliation: Friedrich Miescher Institute, Basel, Switzerland.
authors.forename: X F
authors.initials: XF
authors.lastname: Ming
authors.forename: B M
authors.initials: BM
authors.lastname: Burgering
authors.forename: S
authors.initials: S
authors.lastname: Wennström
authors.forename: L
authors.initials: L
authors.lastname: Claesson-Welsh
authors.forename: C H
authors.initials: CH
authors.lastname: Heldin
authors.forename: J L
authors.initials: JL
authors.lastname: Bos
authors.forename: S C
authors.initials: SC
authors.lastname: Kozma
authors.forename: G
authors.initials: G
authors.lastname: Thomas
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D013552:Swine
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)