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

Author:

Franke Thomas F.1,Kaplan David R.2,Cantley Lewis C.3,Toker Alex3

Affiliation:

1. T. F. Franke, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research Facility and Development Center (NCI-FCRFDC), Frederick, MD 21702, USA; Montreal Neurological Institute, McGill University, PQ H3A 2B4, Canada; and Division of Signal Transduction, Beth Israel Hospital (BIH), Department of Cell Biology, Harvard Medical School (HMS), Boston, MA 02115, USA.

2. D. R. Kaplan, ABL-Basic Research Program, NCI-FCRFDC, Frederick, MD 21702, USA; and Montreal Neurological Institute, McGill University, Montreal, PQ H3A 2B4, Canada.

3. L. C. Cantley and A. Toker, Division of Signal Transduction, BIH, Department of Cell Biology, HMS, Boston, MA 02115, USA.

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-P 2 ) in vivo, and synthetic PtdIns-3,4-P 2 activated Akt both in vitro and in vivo. Binding of PtdIns-3,4-P 2 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-P 2 in vitro, and it was impaired in binding to PtdIns-3,4-P 2 . 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-P 2 and failed to increase Akt activity. Thus, Akt is apparently regulated by the direct interaction of PtdIns-3,4-P 2 with the Akt PH domain.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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