The Structure and Regulation of Protein Phosphatases

Abstract

Four major serine/threonine-specific protein phosphatase catalytic subunits are present in the cytoplasm of animal cells. Three of these enzymes, PP-1, PP-2A, and PP-2B, are members of the same gene family, while PP-2C appears to be distinct. PP-1, PP-2A, and PP-2B are complexed to other subunits in vivo, whereas PP-2C has only been isolated as a monomeric protein. PP-1, PP-2A, and PP-2C have broad and overlapping specificities in vitro, and account for virtually all measurable activity in tissue extracts toward a variety of phosphoproteins that regulate metabolism, muscle contractility, and other processes. Their precise functions in vivo are unknown, although important clues to the physiological roles of PP-1 and PP-2A are provided by the effects of okadaic acid and by the subcellular localization of PP-1. The active forms of PP-1 are largely particulate, and their association with subcellular structures is mediated by "targetting subunits" that direct PP-1 to particular locations, enhance its activity toward certain substrates, and confer important regulatory properties upon it. This concept is best established for the glycogen-bound enzymes in skeletal muscle and liver (PP-1G) and the myofibrillar form (PP-1M) in skeletal muscle. The activities of PP-1 and PP-2B are controlled by the second messengers cyclic AMP and calcium. The activity of PP-2B is dependent on calcium and calmodulin, while PP-1 is controlled in a variety of ways that depend on the form of the enzyme and the tissue. PP-1 can be inhibited by cyclic AMP in a variety of cells through the A-kinase-catalyzed phosphorylation of inhibitor-1 and its isoforms. Phosphorylation of the glycogen-binding subunit of PP-1G by A-kinase promotes translocation of the catalytic subunit from glycogen particles to cytosol in skeletal muscle, inhibiting the dephosphorylation of glycogen-metabolizing enzymes. Allosteric inhibition of hepatic PP-1G by phosphorylase a occurs in response to signals that elevate cyclic AMP or calcium, and prevents the activation of glycogen synthase in liver. PP-1 can also be activated indirectly by calcium through the ability of PP-2B to dephosphorylate inhibitor-1. This control mechanism may operate in dopaminoceptive neurones of the brain and other cells. The inactive cytosolic form of PP-1 (PP-1I) can be activated in vitro through the glycogen synthase kinase-3-catalyzed phosphorylation of its inhibitory subunit (inhibitor-2), but the physiological significance is unclear.(ABSTRACT TRUNCATED AT 400 WORDS)

GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin

“…PP2A is one of four major serine/ threonine protein phosphatases (Cohen, 1989). The catalytic (C) subunit of PP2A is always associated with the constant regulatory A (A) subunit.…”

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

“…In eukaryotes, dephosphorylation at the serine/ threonine sites is largely executed by four major protein phosphatases: phosphatase-1 (PP-1), phosphatase-2A (PP-2A), phosphatase-2B (PP-2B) and phosphatase-2C (PP-2C) (Cohen, 1989;Mumby and Walter, 1993), although other protein phosphatases, including phosphatase-4 (PP-4), phosphatase-5 (PP-5), phosphatase-6 (PP-6) and phosphatase-7 (PP-7), also contribute to this process (Brewis et al, 1993;Bastians and Ponstingl, 1994;Chen et al, 1994;Chinkers, 1994;Huang and Honkananen, 1998). The majority of intracellular protein phosphatase activity has been attributed to PP-1 and PP-2A (Cohen, 1989). Both phosphatases are important in promoting survival because inhibition of the PP-1 and PP-2A activities by either okadaic acid or calyculin A leads to apoptosis of many different types of cells (Gjertsen and Doskeland, 1995).…”

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

“…Several nuclear antigens (EBNA1, -2, -3A and -3C) are apparently essential for B-cell immortalization [34,35]. Lacking significant sequence homology to cellular proteins, however, EBNA2 that is transcribed under the W promoter after initial infection of EBV stimulates the bi-directional viral latency C promoter and the LMP2A promoter, thereby transactivating both LMP1 and LMP2A [36].…”