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

PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) is a critical serine/threonine phosphatase that serves as a major negative regulator of the PI3K/Akt signaling pathway (UniProt O60346). By specifically dephosphorylating the hydrophobic motif of Akt at Ser-473, PHLPP1 terminates Akt activity, thereby promoting apoptosis and inhibiting cell proliferation (PubMed: 17350576). Beyond Akt, PHLPP1 also regulates other AGC kinases such as Protein Kinase C (PKC) and S6K1, and it plays a role in modulating the pro-apoptotic kinase Mst1 (PubMed: 21333914). In the context of oncology, PHLPP1 is frequently characterized as a tumor suppressor, and its expression is often lost or downregulated in various malignancies, including prostate, colon, and breast cancers (PubMed: 18042445). While there are currently no FDA-approved drugs targeting PHLPP1, small molecule inhibitors like NSC 117079 are utilized in research to explore its potential as a therapeutic target for neuroprotection and regenerative medicine (PubMed: 23839033). Its diverse roles in metabolism and circadian rhythms suggest that therapeutic modulation of PHLPP1 requires careful consideration of systemic safety profiles.

Other names

PHLPPPLEKHE1SCOPSuprachiasmatic nucleus circadian oscillatory proteinPPM3AProtein phosphatase, Mg2+/Mn2+ dependent 3A

Dephosphorylation of the hydrophobic motif (Ser-473) of Akt, leading to its inactivation and the subsequent suppression of the PI3K/Akt signaling pathway (PubMed: 17350576). It also dephosphorylates and inactivates Protein Kinase C (PKC) and dephosphorylates the pro-apoptotic kinase Mst1 (PubMed: 21333914).