title: Tyrosine phosphorylation-dependent and -independent role of Shc in the regulation of IGF-1-induced mitogenesis and glycogen synthesis.
abstract: To examine the functional role of Shc tyrosine phosphorylation in IGF-1 signaling, wild-type (WT)-Shc and Y239,240,317F (3F)-Shc were transiently transfected into L6 myoblasts. IGF-1 signaling was compared among the transfected cells. IGF-1-induced tyrosine phosphorylation of Shc and its subsequent association with Grb2 were increased in WT-Shc cells, whereas they were decreased in 3F-Shc cells compared with those in parental L6 cells. Consistent with their changes, IGF-1-induced MAPK activation and thymidine incorporation were enhanced in WT-Shc cells, whereas they were again decreased in 3F-Shc cells. It is possible that Shc and insulin receptor substrate (IRS)-1 can interact competitively, via their phosphotyrosine binding (PTB) domains, with the activated IGF-1 receptor. In this regard, IGF-1-induced tyrosine phosphorylation of IRS-1 was decreased by overexpressing both WT-Shc and 3F-Shc cells. Consistent with the decrease, IGF-1-induced IRS-1 association with the p85 subunit of PI3K and activation of PI3K and Akt were reduced in both WT-Shc and 3F-Shc cells. As a result, IGF-1-induced glycogen synthesis was also decreased in both cells. Furthermore, expression of Shc PTB domain alone inhibited IGF-1 stimulation of Akt and glycogen synthesis. These results indicate that tyrosine phosphorylation of Shc is important for IGF-1 stimulation of MAPK leading to mitogenesis and that Shc, via its PTB domain, negatively regulates IGF-1-induced glycogen synthesis by competing with IRS-1, which is not relevant to Shc tyrosine phosphorylation.
authors.affiliation: First Department of Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan. tsasaoka-tym@umin.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Sasaoka
authors.forename: M
authors.initials: M
authors.lastname: Ishiki
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: H
authors.initials: H
authors.lastname: Hori
authors.forename: H
authors.initials: H
authors.lastname: Hirai
authors.forename: T
authors.initials: T
authors.lastname: Haruta
authors.forename: H
authors.initials: H
authors.lastname: Ishihara
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D006003:Glycogen / Q000096:biosynthesis*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D012016:Reference Values; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; D006003:Glycogen; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; C495948:GRB2 protein, human; C526292:IRS1 protein, human; C528024:SHC1 protein, human; C494918:AKT1 protein, human