The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2

Ian H. Batty (1) , Jeroen van Der Kaay , Alex Gray , Joan F. Telfer , Miles J. Dixon , C. Peter Downes

1 The Division of Molecular Physiology, School of Life Sciences

Activation of class Ia phosphoinositide 3-kinase (PI3K) produces PtdInsP 3}, a vital intracellular mediator whose degradation generates additional lipid signals. Vanadate analogues that inhibit protein tyrosine phosphatases (PTPs) were used to probe the mechanisms which regulate the concentrations of these molecules allowing their independent or integrated function. In 1321N1 cells which lack PtdInsP 3} 3-phosphatase activity, sodium vanadate or a cell permeable derivative, potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) (bpV(phen)), increased the recruitment into antiphosphotyrosine immunoprecipitates of PI3K activity and of the p85 and p110α subunits of class Ia PI3K and enhanced the recruitment of PI3K activity stimulated by PDGF (platelet derived growth factor). However, neither inhibitor much increased cellular PtdInsP 3} concentrations but both diminished dramatically the accumulation of PtdInsP 3} stimulated by PDGF or insulin and increased markedly the control and stimulated concentrations of PtdIns(3,4)P 2}. These actions were accounted for by the ability of PTP inhibitors to stimulate the activity of endogenous PtdInsP 3} 5-phosphatase(s), particularly SHIP2 (Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2) and to inhibit types I and II PtdIns(3,4)P 2} 4-phosphatases. Thus, bpV(phen) promoted the translocation of SHIP2 from the cytosol to a Triton X-100 - insoluble fraction and induced a marked (5-10 fold) increase in SHIP2 specific activity mediated by enhanced tyrosine phosphorylation. The net effect of these inhibitors was, therefore, to switch the signal output of class I PI3K from PtdInsP 3} to PtdIns(3,4)P 2}. A key component controlling this shift in the balance of lipid signals is the activation of SHIP2 by increased tyrosine phosphorylation, an effect observed in HeLa cells in response to both PTP inhibitors and epidermal growth factor.

Mots clés: Life Sciences

Ian H. Batty, Jeroen van Der Kaay, Alex Gray, Joan F. Telfer, Miles J. Dixon, et al.. The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2. Biochemical Journal, 2007, 407 (2), pp.255-266. ⟨10.1042/BJ20070558⟩. ⟨hal-00478793⟩