PHLPP2 or PH domain and leucine rich repeat protein phosphatase 2 is the important regulators of Akt serine-threonine kinases and conventional/novel protein kinase C (PKC) isoforms. PHLPP1 and PHLPP2 differentially regulated AKT signaling by selectively dephosphorylating the hydrophobic motifs of AKT2 or AKT3. PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.