Abstract
The regulation of the serine-threonine kinase Akt by lipid products of phosphoinositide 3-kinase (PI 3-kinase) was investigated. Akt activity was found to correlate with the amount of phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P2) in vivo, and synthetic PtdIns-3,4-P2 activated Akt both in vitro and in vivo. Binding of PtdIns-3,4-P2 occurred within the Akt pleckstrin homology (PH) domain and facilitated dimerization of Akt. Akt mutated in the PH domain was not activated by PI 3-kinase in vivo or by PtdIns-3, 4-P2 in vitro, and it was impaired in binding to PtdIns-3,4-P2. Examination of the binding to other phosphoinositides revealed that they bound to the Akt PH domain with much lower affinity than did PtdIns-3,4-P2 and failed to increase Akt activity. Thus, Akt is apparently regulated by the direct interaction of PtdIns-3,4-P2 with the Akt PH domain.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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COS Cells
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Dimerization
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Enzyme Activation
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Mice
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Phosphatidylinositol 3-Kinases
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Phosphatidylinositol Phosphates / metabolism*
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Phosphatidylinositol Phosphates / pharmacology
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Platelet-Derived Growth Factor / pharmacology
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Point Mutation
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
Substances
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Phosphatidylinositol Phosphates
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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phosphatidylinositol 3,4,5-triphosphate
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phosphatidylinositol 3,4-diphosphate
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Phosphotransferases (Alcohol Group Acceptor)
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt