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Phosphatidylinositol (3,4,5)P Is Essential but Not Sufficient for Protein Kinase B (PKB) Activation; Phosphatidylinositol (3,4)P Is Required for PKB Phosphorylation at Ser-473 - Studies Using Cells From SH2-Containing Inositol-5-Phosphatase Knockout Mice

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Huber,  Michael
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Neilsen,  Paul
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Prestwich,  Glenn D.
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Krystal,  Gerald
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Scheid, M. P., Huber, M., Damen, J. E., Hughes, M., Kang, V., Neilsen, P., et al. (2002). Phosphatidylinositol (3,4,5)P Is Essential but Not Sufficient for Protein Kinase B (PKB) Activation; Phosphatidylinositol (3,4)P Is Required for PKB Phosphorylation at Ser-473 - Studies Using Cells From SH2-Containing Inositol-5-Phosphatase Knockout Mice. Journal of Biological Chemistry, 277(11), 9027-9035.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-965B-9
Abstract
Using bone marrow derived mast cells from SH2-containing inositol-5-phosphatase (SHIP) +/+ and -/- mice, we found that the loss of SHIP leads to a dramatic increase in Steel Factor (SF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P), a substantial reduction in PI(3,4)P, and no change in PI(4,5)P levels. We also found that SF-induced activation of protein kinase B (PKB) is increased and prolonged in SHIP-/- cells, due in large part to more PKB associating with the plasma membrane in these cells. Pretreatment of SHIP-/- cells with 25 μΜ LY294002 resulted in complete inhibition of SF-induced PI(3,4)P, while still yielding PI(3,4,5)P levels similar to those achieved in SHIP+/+ cells. This offered a unique opportunity to study the regulation of PKB by PI(3,4,5)P, in the absence of PI(3,4)P. Under these conditions, PKB activity was markedly reduced compared with that in SF-stimulated SHIP+/+ cells, even though more PKB localized to the plasma membrane. Although phosphoinositide- dependent kinase I mediated phosphorylation of PKB at Thr-308 was unaffected by LY294002, phosphorylation at Ser-473 was dramatically reduced. Moreover, intracellular delivery of PI(3,4)P to LY294002-pretreated, SF-stimulated SHIP-/- cells increased phosphorylation of PKB at Ser-473 and increased PKB activity. These results are consistent with a model in which SHIP serves as a regulator of both activity and subcellular localization of PKB.