title: Dual role of SRC homology domain 2-containing inositol phosphatase 2 in the regulation of platelet-derived growth factor and insulin-like growth factor I signaling in rat vascular smooth muscle cells.
abstract: Src homology domain 2 (SH2)-containing inositol phosphatase 2 (SHIP2) possesses 5-phosphatase activity and an SH2 domain. The role of SHIP2 in platelet-derived growth factor (PDGF) and IGF-I signaling was studied by expressing wild-type (WT-) and a catalytically defective (Delta IP-) SHIP2 into rat aortic smooth muscle cells by adenovirus-mediated gene transfer. PDGF- and IGF-I-induced tyrosine phosphorylation of their respective receptors and phosphatidylinositol 3-kinase (PI3-kinase) activity were not affected by the expression of either WT- or Delta IP-SHIP2. SHIP2 possessed 5'-phosphatase activity to hydrolyze the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate in vivo. Akt and glycogen synthase kinase 3beta are known to be downstream molecules of PI3-kinase, leading to the antiapoptotic effect. Overexpression of WT-SHIP2 inhibited PDGF- and IGF-I-induced phosphorylation of these molecules and the protective effect of poly(ADP-ribose) polymerase degradation, whereas these phosphorylations and the protective effect were enhanced by the expression of Delta IP-SHIP2, which functions in a dominant negative fashion. Regarding the Ras-MAPK pathway, PDGF- and IGF-I-induced tyrosine phosphorylation of Shc was not affected by the expression of either WT- or Delta IP-SHIP2, whereas both expressed SHIP2 associated with Shc. Importantly, PDGF and IGF-I stimulation of Shc/Grb2 binding, MAPK activation, and 5-bromo-2'-deoxyuridine incorporation were all decreased in both WT- and Delta IP-SHIP2 expression. These results indicate that SHIP2 plays a negative regulatory role in PDGF and IGF-I signaling in vascular smooth muscle cells. As the bifunctional role, our results suggest that SHIP2 regulates PDGF- and IGF-I-mediated signaling downstream of PI3-kinase, leading to the antiapoptotic effect via 5-phosphatase activity, and that SHIP2 regulates the growth factor-induced Ras-MAPK pathway mainly via the SH2 domain.
authors.affiliation: Department of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. tsasaoka-tym@umin.ac.jp
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Kosei
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hori
authors.forename: Shihou
authors.initials: S
authors.lastname: Murakami
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Fukui
authors.forename: Hajime
authors.initials: H
authors.lastname: Ishihara
authors.forename: Rina
authors.initials: R
authors.lastname: Aota
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kimura
authors.forename: Masashi
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D001013:Aorta, Thoracic / Q000166:cytology; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002478:Cells, Cultured; D051380:GRB2 Adaptor Protein; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018909:src Homology Domains / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D051380:GRB2 Adaptor Protein; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007004:Hypoglycemic Agents; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D010982:Platelet-Derived Growth Factor; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C495950:Grb2 protein, rat; C060974:phosphatidylinositol 3,4,5-triphosphate; C494920:Akt1 protein, rat; C000605506:GSK3B protein, human; C000605508:Gsk3b protein, rat; C098706:INPPL1 protein, human