title: Oncogenic Met receptor induces cell-cycle progression in Xenopus oocytes independent of direct Grb2 and Shc binding or Mos synthesis, but requires phosphatidylinositol 3-kinase and Raf signaling.
abstract: Biological responses of hepatocyte growth factor (HGF) are mediated by the Met receptor tyrosine kinase. Although HGF is a potent mitogen for a variety of cells, the signals required for cell-cycle progression by the Met/HGF receptor are poorly defined. In this study, we have used the Xenopus oocyte system to define the role of various Met proximal-binding partners and downstream signaling pathways in cell-cycle regulation. We show that cell-cycle progression and activation of MAPK and JNK mediated by the oncogenic Met receptor, Tpr-Met, are dependent on its kinase activity and the presence of the twin phosphotyrosine (Y482 & Y489) residues in its C-terminus, but that the recruitment of Grb2 and Shc adaptor proteins is dispensable, implicating other signaling molecules. However, using Met receptor oncoproteins engineered to recruit specific signaling proteins, we demonstrate that recruitment of Grb2 or Shc adaptor proteins is sufficient to induce cell-cycle progression and activation of MAPK and JNK, while the binding of phospholipase-Cgamma or phosphatidylinositol 3-kinase alone fails to elicit these responses. Using various means to block phosphatidylinositol 3-kinase, phospholipase-Cgamma, MEK, JNK, Mos, and Raf1 activity, we show that unlike the fibroblast growth factor receptor, MEK-dependent and independent signaling contribute to Met receptor-mediated cell-cycle progression, but phospholipase-Cgamma or JNK activity and Mos synthesis are not critical. Notably, we demonstrate that Raf1 and phosphatidylinositol 3-kinase signaling are required for cell-cycle progression initiated by the Met receptor, a protein frequently deregulated in human tumors.
authors.affiliation: Laboratory of Protein Dynamics and Signaling, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mood
authors.forename: Caroline
authors.initials: C
authors.lastname: Saucier
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ishimura
authors.forename: Yong-Sik
authors.initials: YS
authors.lastname: Bong
authors.forename: Hyun-Shik
authors.initials: HS
authors.lastname: Lee
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Ira O
authors.initials: IO
authors.lastname: Daar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011374:Progesterone / Q000494:pharmacology; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017231:Proto-Oncogene Proteins c-mos / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016203:CDC2 Protein Kinase; D002867:Chromones; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D051380:GRB2 Adaptor Protein; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048055:Mitogen-Activated Protein Kinase 8; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D011374:Progesterone; D019859:Proto-Oncogene Proteins c-met; D017231:Proto-Oncogene Proteins c-mos; D019908:Proto-Oncogene Proteins c-raf; D016372:RNA, Antisense; D012333:RNA, Messenger; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D029867:Xenopus Proteins; C528024:SHC1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C495329:Mos protein, Xenopus