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

• Published in: Endocrinology (Philadelphia) 2003-09, Vol.144 (9), p.4204-4214
• Main Authors: Sasaoka, Toshiyasu, Kikuchi, Kosei, Wada, Tsutomu, Sato, Akira, Hori, Hiroyuki, Murakami, Shihou, Fukui, Kazuhito, Ishihara, Hajime, Aota, Rina, Kimura, Ikuko, Kobayashi, Masashi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Signal Transducing; Adenoviridae - genetics; AKT protein; Animals; Antimetabolites - pharmacokinetics; Aorta; Aorta, Thoracic - cytology; Biological and medical sciences; Blood vessels and receptors; Bromodeoxyuridine - pharmacokinetics; Cells, Cultured; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Gene transfer; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycogens; GRB2 Adaptor Protein; Grb2 protein; Growth factors; Homology; Hypoglycemic Agents - pharmacology; Inositol; Inositol polyphosphate 5-phosphatase; Inositols; Insulin - pharmacology; Insulin-like growth factor I; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; Kinases; MAP kinase; Mitogen-Activated Protein Kinases - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - enzymology; Muscles; myo-Inositol-1 (or 4)-monophosphatase; Phosphatase; Phosphatidylinositol 3,4,5-triphosphate; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - metabolism; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Platelet-derived growth factor; Platelet-Derived Growth Factor - pharmacology; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - metabolism; Protein-Serine-Threonine Kinases; Protein-tyrosine-phosphatase; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Ribose; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Smooth muscle; src Homology Domains - physiology; Tyrosine; Vertebrates: cardiovascular system; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0190

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 (ΔIP-) 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 ΔIP-SHIP2. SHIP2 possessed 5′-phosphatase activity to hydrolyze the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate in vivo. Akt and glycogen synthase kinase 3β 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 ΔIP-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 ΔIP-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 ΔIP-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.