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

PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is a serine/threonine phosphatase that functions as a critical homeostatic regulator of the PI3K/Akt signaling pathway. By specifically dephosphorylating the hydrophobic motif (Ser473) of Akt, PHLPP1 terminates Akt signaling, thereby inhibiting cell survival and promoting apoptosis (UniProt: Q86V11). It also regulates other AGC kinases, such as Protein Kinase C (PKC) and Mst1, influencing diverse processes from circadian rhythms to chondrocyte differentiation (PubMed: 21333914). In clinical contexts, PHLPP1 is often viewed as a tumor suppressor, and its loss is frequently observed in cancers like prostate and breast cancer, leading to hyperactivated Akt signaling (PubMed: 15647271). Conversely, its upregulation is associated with insulin resistance in type 2 diabetes, making it a potential target for metabolic therapies (PubMed: 17384581). While no PHLPP1-targeted drugs are currently FDA-approved, small molecule inhibitors like NSC117079 are used in preclinical research to explore its potential in treating neurodegeneration and metabolic disorders (PubMed: 23911544). The target's ability to selectively modulate Akt isoforms makes it a high-interest candidate for precision medicine in both oncology and regenerative medicine.

Other names

PHLPPPLEKHE1SCOPSuprachiasmatic nucleus circadian oscillatory proteinPH domain leucine-rich repeat-containing protein phosphatase 1

Small molecule inhibition of the phosphatase activity to prevent dephosphorylation of Akt at Ser473, thereby enhancing Akt-mediated survival and metabolic signaling.