PHLPP2
Description
The PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2) is a protein-coding gene located on chromosome 16.
PHLPP isoforms (PH domain and Leucine rich repeat Protein Phosphatases) are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases (Akt1, Akt2, Akt3) and conventional/novel protein kinase C (PKC) isoforms. 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. PHLPP dephosphorylates Ser-473 (the hydrophobic motif) in Akt, thus partially inactivating the kinase. In addition, PHLPP dephosphorylates conventional and novel members of the protein kinase C family at their hydrophobic motifs, corresponding to Ser-660 in PKCβII. PHLPP is a member of the PPM family of phosphatases, which requires magnesium or manganese for their activity and are insensitive to most common phosphatase inhibitors, including [okadaic acid]. PHLPP1 and PHLPP2 have a similar domain structure, which includes a putative Ras association domain, a pleckstrin homology domain, a series of leucine-rich repeats, a PP2C phosphatase domain, and a C-terminal PDZ ligand. PHLPP1 has two splice variants, PHLPP1α and PHLPP1β, of which PHLPP1β is larger by approximately 1.5 kilobase pairs. PHLPP1α, which was the first PHLPP isoform to be characterized, lacks the N-terminal portion of the protein, including the Ras association domain. PHLPP's domain structure influences its ability to dephosphorylate its substrates. A PHLPP construct lacking the PH domain is unable to decrease PKC phosphorylation, while PHLPP lacking the PDZ ligand is unable to decrease Akt phosphorylation. The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly dephosphorylate, and therefore inactivate, distinct Akt isoforms, at one of the two critical phosphorylation sites required for activation: Serine473.
PHLPP2 is a protein phosphatase that regulates Akt and PKC signaling by dephosphorylating specific residues in the C-terminal hydrophobic motif of AGC Ser/Thr protein kinases. It dephosphorylates Ser-473 of AKT1, Ser-660 of PRKCB isoform beta-II, and Ser-657 of PRKCA. Dephosphorylation of Ser-473 in Akt triggers apoptosis and decreases cell proliferation. PHLPP2 also regulates the phosphorylation of AKT3, dephosphorylates STK4 at Thr-387, leading to STK4 activation and apoptosis, and dephosphorylates RPS6KB1, regulating cap-dependent translation. PHLPP2 inhibits cancer cell proliferation and may act as a tumor suppressor. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. PHLPP2 dephosphorylates RAF1, inhibiting its kinase activity.
PHLPP2 is also known as PHLPPL, PPM3B.
