Type 2A protein phosphatase, the complex regulator of numerous signaling pathways

Type 2A protein phosphatase (PP2A) comprises a diverse family of phosphoser ine- and phosphothreonine-specific enzymes ubiquitously expressed in eukary otic cells. Common to all forms of PP2A is a catalytic subunit (PP2Ac) whic h can form two distinct complexes, one with a structural subunit termed PR6 5/A and another with an alpha4 protein. The PR65/A-PP2Ac dimer may further associate with a regulatory subunit and form a trimeric holoenzyme. To date , three distinct families of regulatory subunits, which control substrate s electivity and phosphatase activity and target PP2A holoenzymes to their su bstrates, have been identified. Other molecular mechanisms that regulate PP 2Ac function include phosphorylation, carboxyl methylation, inhibition by i ntracellular protein inhibitors (I-1(PP2A) and I-2(PP2A)), and stimulation by ceramide. PP2A dephosphorylates many proteins in vitro, but in vivo prot ein kinases and transcription factors appear to represent two major sets of substrates. Several natural compounds can inhibit PP2A activity and are us ed to study its function. Mutations in genes encoding PR65/A subunits have been identified in several different human cancers and the PP2A inhibitor, termed fostriecin, is being rested as an anticancer drug. Thus, a more thor ough understanding of PP2A structure and function may lead to the developme nt of novel strategies against human diseases. BIOCHEM PHARMACOL 60;8:1225- 1235, 2000. (C) 2000 Elsevier Science Inc.