PT  - JOURNAL ARTICLE
AU  - Franke, Thomas F.
AU  - Kaplan, David R.
AU  - Cantley, Lewis C.
AU  - Toker, Alex
TI  - Direct Regulation of the <em>Akt</em> Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate
AID  - 10.1126/science.275.5300.665
DP  - 1997 Jan 31
TA  - Science
PG  - 665--668
VI  - 275
IP  - 5300
4099  - http://science.sciencemag.org/content/275/5300/665.short
4100  - http://science.sciencemag.org/content/275/5300/665.full
SO  - Science1997 Jan 31; 275
AB  - 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.