Pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1)

Pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) is a member of the PP2C family of serine/threonine phosphatases that serves as a critical regulator of the PI3K/Akt signaling pathway. It functions by specifically dephosphorylating the hydrophobic motif of Akt (Ser-473), as well as protein kinase C (PKC) and Mst1, thereby terminating pro-survival and pro-growth signals (UniProt O60346). In the context of oncology, PHLPP1 is widely recognized as a tumor suppressor; its downregulation or deletion is frequently observed in prostate, colorectal, and breast cancers, leading to constitutive Akt activation (PubMed: 15808815). Beyond cancer, PHLPP1 plays a significant role in metabolic regulation, where its overexpression in skeletal muscle is linked to insulin resistance and type 2 diabetes (PubMed: 21566074). It also influences circadian rhythms by regulating the phosphorylation of clock-related proteins in the suprachiasmatic nucleus (PubMed: 15657444). While there are currently no FDA-approved drugs targeting PHLPP1, experimental small-molecule inhibitors like NSC117079 have been used in research to study its role in cell signaling and potential as a therapeutic target for metabolic and neurodegenerative disorders (PubMed: 28843051). The primary therapeutic challenge lies in achieving isoform specificity and managing the risk of oncogenesis if the phosphatase is inhibited systemically.

Other names

PHLPPSCOPPLEKHE1Suprachiasmatic nucleus circadian oscillatory proteinPH domain and leucine-rich repeat protein phosphatase 1

Dephosphorylation of the hydrophobic motif (Ser-473) of Akt, leading to its inactivation and subsequent inhibition of cell survival and growth pathways.