[en] SHIP2, the ubiquitous SH2 domain containing inositol 5-phosphatase, includes a series of protein interacting domains and has the ability to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] in vitro. The present study, which was undertaken to evaluate the impact of SHIP2 on PtdIns(3,4,5)P3 levels, was performed in a mouse embryonic fibroblast (MEF) model using SHIP2 deficient (– ⁄ –) MEF cells derived from knockout mice. PtdIns(3,4,5)P3 was upregulated in serum stimulated – ⁄ – MEF cells as compared to +⁄+ MEF cells. Although the absence of SHIP2 had no effect on basal PtdIns(3,4,5)P3 levels, we show here that this lipid was significantly upregulated in SHIP2 – ⁄ – cells but only after short-term (i.e. 5–10 min) incubation with serum. The difference in PtdIns(3,4,5)P3 levels in heterozygous fibroblast cells was intermediate between the +⁄+ and the – ⁄ – cells. In our model, insulin-like growth factor-1 stimulation did not show this upregulation. Serum stimulated phosphoinositide 3-kinase (PI 3-kinase) activity appeared to be comparable between +⁄+ and – ⁄ – cells. Moreover, protein kinase B, but not mitogen activated protein kinase activity, was also potentiated in SHIP2 deficient cells stimulated by serum. The upregulation of protein kinase B activity in serum stimulated cells was totally reversed in the presence of the PI 3-kinase inhibitor LY-294002, in both +⁄+ and – ⁄ – cells. Altogether, these data establish a link between SHIP2 and the acute control of PtdIns(3,4,5)P3 levels in intact cells
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