Activation of class Ia PI3K (phosphoinositide 3-kinase) produces PtdInsP3, a vital intracellular mediator whose degradation generates additional lipid signals. In the present study vanadate analogues that inhibit PTPs (protein tyrosine phosphatases) were used to probe the mechanisms which regulate the concentrations of these molecules allowing their independent or integrated function. In 1321N1 cells, which lack PtdInsP3 3-phosphatase activity, sodium vanadate or a cell permeable derivative, bpV(phen) [potassium bisperoxo(1,10-phenanthroline)oxovanadate (V)], increased the recruitment into anti-phosphotyrosine 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 PtdInsP3 concentrations, but both diminished dramatically the accumulation of PtdInsP3 stimulated by PDGF or insulin and markedly increased the control and stimulated concentrations of PtdIns(3,4)P2. These actions were accounted for by the ability of PTP inhibitors to stimulate the activity of endogenous PtdInsP3 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)P2 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 PtdInsP3 to PtdIns(3,4)P2. 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.
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Research Article|
September 25 2007
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;
1The Division of Molecular Physiology, School of Life Sciences, The James Black Centre, University of Dundee, Dow St, Dundee DD1 5EH, Scotland, U.K.
2To whom correspondence should be addressed (email i.h.batty@dundee.ac.uk).
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Jeroen van der Kaay;
Jeroen van der Kaay
1
1The Division of Molecular Physiology, School of Life Sciences, The James Black Centre, University of Dundee, Dow St, Dundee DD1 5EH, Scotland, U.K.
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Alex Gray;
Alex Gray
1The Division of Molecular Physiology, School of Life Sciences, The James Black Centre, University of Dundee, Dow St, Dundee DD1 5EH, Scotland, U.K.
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Joan F. Telfer;
Joan F. Telfer
1The Division of Molecular Physiology, School of Life Sciences, The James Black Centre, University of Dundee, Dow St, Dundee DD1 5EH, Scotland, U.K.
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Miles J. Dixon;
Miles J. Dixon
1The Division of Molecular Physiology, School of Life Sciences, The James Black Centre, University of Dundee, Dow St, Dundee DD1 5EH, Scotland, U.K.
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C. Peter Downes
C. Peter Downes
1The Division of Molecular Physiology, School of Life Sciences, The James Black Centre, University of Dundee, Dow St, Dundee DD1 5EH, Scotland, U.K.
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Publisher: Portland Press Ltd
Received:
April 25 2007
Revision Received:
August 01 2007
Accepted:
August 02 2007
Accepted Manuscript online:
August 02 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem J (2007) 407 (2): 255–266.
Article history
Received:
April 25 2007
Revision Received:
August 01 2007
Accepted:
August 02 2007
Accepted Manuscript online:
August 02 2007
Citation
Ian H. Batty, Jeroen van der Kaay, Alex Gray, Joan F. Telfer, Miles J. Dixon, C. Peter Downes; The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2. Biochem J 15 October 2007; 407 (2): 255–266. doi: https://doi.org/10.1042/BJ20070558
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