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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.

Authors: Sasaoka, T  Kikuchi, K  Wada, T  Sato, A  Hori, H  Murakami, S  Fukui, K  Ishihara, H  Aota, R  Kimura, I  Kobayashi, M 
Citation: Sasaoka T, etal., Endocrinology. 2003 Sep;144(9):4204-14.
Pubmed: (View Article at PubMed) PMID:12933696
DOI: Full-text: 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 (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.


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RGD Object Information
RGD ID: 1626126
Created: 2007-07-12
Species: All species
Last Modified: 2007-07-12
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.