PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2)

PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2) is a large multidomain protein originally classified as a serine/threonine phosphatase, proposed to regulate key cell signaling pathways such as PI3K-Akt and PKC by direct dephosphorylation of terminal hydrophobic motifs on protein kinases. Recent biochemical and structural studies demonstrate that PHLPP2 contains a single zinc ion in its catalytic site and lacks measurable phosphatase activity in vitro, instead acting as a pseudophosphatase likely to have scaffolding roles at the membrane and in multi-protein complexes. Classical functional attributions, such as direct tumor suppressor or kinase regulator, may be inaccurate for physiological PHLPP2 in mammals. Its structure comprises a Ras-association (RA) domain, a PH domain, leucine-rich repeats (LRR), and a C-terminal PP2C-like domain, but the protein appears to have lost key catalytic residues in evolution, differentiating its molecular mechanism from canonical phosphatases. The exact physiological roles of PHLPP2 remain under active investigation.

Other names

KIAA0931PHLPPLPHLPP-likePPM3Bprotein phosphatase, Mg2+/Mn2+-dependent 3BPH domain and leucine-rich repeat protein phosphatase 2

historical drug targeting focused on inhibiting or enhancing phosphatase activity for modulating Akt/PKC signaling, but this mechanism is unsupported for PHLPP2 due to lack of evident enzymatic activity