Direct Regulation of the Akt Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate

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.

[1]  M. Czech,et al.  Mouse p170 Is a Novel Phosphatidylinositol 3-Kinase Containing a C2 Domain* , 1996, The Journal of Biological Chemistry.

[2]  H. Matsuzaki,et al.  Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Toker,et al.  Phosphorylation of the Platelet p47 Phosphoprotein Is Mediated by the Lipid Products of Phosphoinositide 3-Kinase (*) , 1995, The Journal of Biological Chemistry.

[4]  M. Andjelkovic,et al.  Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Andrius Kazlauskas,et al.  The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase , 1995, Cell.

[6]  P. Majerus,et al.  The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Camilli,et al.  A presynaptic inositol-5-phosphatase , 1996, Nature.

[8]  J. Downward.  A target for Pl(3) kinase , 1995, Nature.

[9]  J. Downward,et al.  Activation of phosphoinositide 3‐kinase by interaction with Ras and by point mutation. , 1996, The EMBO journal.

[10]  J. Bos.  A target for phosphoinositide 3-kinase: Akt/PKB. , 1995, Trends in biochemical sciences.

[11]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[12]  A. Edelman,et al.  5′-AMP Activates the AMP-activated Protein Kinase Cascade, and Ca2+/Calmodulin Activates the Calmodulin-dependent Protein Kinase I Cascade, via Three Independent Mechanisms (*) , 1995, The Journal of Biological Chemistry.

[13]  David R. Kaplan,et al.  Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt , 1997, Science.