After PtdIns(3,4,5)P3 (PIP3 ) binding to Akt PH domain, membrane-bound Akt is phosphorylated at the C-terminus (Ser473 in Akt1) and at the activation loop (Thr308 in Akt1) by PDK1 and mTORC2 respectively and in a co-ordinated manner. Membrane localization also promotes the formation of a phosphatase-resistant cage to shield both phosphorylated sites from phosphatases. In the absence of phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ), cytosolic phosphorylated Akt is dephosphorylated by phosphatases. DDDW-modified Akt C-terminus promotes phosphatase resistance at the activation loop.