PHLPP2

PHLPP2, or PH domain and leucine-rich repeat protein phosphatase 2, is a human serine/threonine protein phosphatase and a member of the PHLPP family, which also includes PHLPP1. The PHLPP enzymes are atypical protein phosphatases characterized by an N-terminal PH domain and several leucine-rich repeats, with a catalytic PP2C-like domain responsible for phosphatase activity. PHLPP2 localizes mainly in the cytoplasm and at membranes, where it can interact with signaling complexes.

PHLPP2 functions as a negative regulator of key signaling pathways by dephosphorylating substrates such as AKT at Ser473, thereby reducing AKT signaling and influencing cell survival and apoptosis. It also targets certain protein kinase C (PKC) isoforms, contributing to downregulation of PKC signaling. Through these actions, PHLPP2 modulates processes including cell growth, metabolism, and responses to cellular stress, and it may interact with other AGC kinases and control nodes involved in the cell cycle and apoptosis.

Regulation of PHLPP2 activity occurs at multiple levels, including changes in expression, subcellular localization, and interactions with scaffold proteins via C-terminal regulatory motifs. Altered PHLPP2 expression has been observed in various cancers and can affect cellular responses to therapies that rely on AKT signaling.

Clinical and research relevance: Because AKT signaling is a central driver of tumorigenesis in many cancers, PHLPP2 is studied for its potential tumor-suppressive role. The protein is also investigated for roles in cardiovascular, metabolic, and nervous system function, where precise control of AKT and PKC signaling is important.