Disease relevance of PPP2CA

• Alpha4 phosphoprotein in the mTOR pathway is a prolactin (PRL)-downregulated gene product that interacts with the catalytic subunit of serine/threonine protein phosphatase 2A (PP2Ac) in rat Nb2 lymphoma cells [1].
• Additionally, ectopic PP2Ac enhances activation of HIV-1 provirus by PMA [2].
• Relative to wild-type PP2Ac, the active-site mutants were dramatically overexpressed in High Five insect cells using the baculovirus system [3].
• We have recently shown that in colon cancer cells, Vitamin D receptor (VDR) interacts with the catalytic subunit of Ser/Thr protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner [4].

Psychiatry related information on PPP2CA

• METHODS: This prospective, naturalistic study of the treatment of postnatal depression compared 30 women treated at a specialised psychiatric day hospital with 30 women treated using routine primary care (RPC) [5].
• RESULTS: Compared with RPC, the PEG significantly reduced the level of depressive symptoms, but had no impact on psychosocial outcome [6].

High impact information on PPP2CA

• Elevated PP2Ac causes hypophosphorylation of MAPs, a pathological mechanism that is consistent with the OS phenotype [7].
• By deletion analysis, the binding domains were found to be located within the 50 N-terminal amino acids of PP2Ac, and between amino acid residues 338 and 381 in the C-terminal part of human eRF1 [8].
• In addition to the 36 kDa catalytic subunit (PP2Ac) and established regulatory subunits of 65 kDa (PR65) and 55 kDa (PR55), purified preparations contained two proteins with apparent Mrs of 54 and 55 kDa [8].
• Our results imply that differential methylation of PP2Ac occurs at the G0/G1 and G1/S boundaries [9].
• Monospecific and affinity-purified antibodies against both PP2Ac and PR65 show that these proteins are ubiquitously localized in the cytoplasm and the nucleus in nontransformed fibroblasts [9].

Biological context of PPP2CA

• We demonstrate here that RP-C is identical to the catalytic subunit of cellular protein phosphatase 2A (PP2Ac) [10].
• We also show that purified RP-C/PP2Ac preferentially stimulates SV40 DNA replication in extracts from early G1 phase cells [10].
• Other molecular mechanisms that regulate PP2Ac function include phosphorylation, carboxyl methylation, inhibition by intracellular protein inhibitors (I(1)(PP2A) and I(2)(PP2A)), and stimulation by ceramide [11].
• Detailed analysis of synchronized cells reveals striking changes in the nuclear to cytoplasmic ratio of PP2Ac-specific immunoreactivity albeit the total amounts of neither PP2Ac nor PR65 in each compartment alters significantly during the cell cycle [9].
• Finally, we demonstrate that the endogenous VDR, PP1c or PP2Ac, and p70(S6k) are present in a ternary complex in vivo, and the interaction of p70(S6k) with the VDR-PP complex is modulated by the phosphorylation state of the kinase [12].

Anatomical context of PPP2CA

• Immunostaining of PP2Ac or of PP2Aa + c overexpressing HPAEC indicated actin cytoskeleton rearrangement [13].
• Transient overexpression of alpha4 in COS-1 cells had no effect on endogenous PP2Ac protein levels but significantly increased PP2Ac carboxymethylation and PP2A activity as compared to controls [1].
• A trimeric protein phosphatase 2A (PP2A(T55)) composed of the catalytic (PP2Ac), structural (PR65/A), and regulatory (PR55/B) subunits was isolated from rabbit skeletal muscle by thiophosphorylase affinity chromatography, and contained two additional proteins of 54 and 55 kDa, respectively [14].
• Thus, our findings indicate that Hsp90 functions to balance the phosphorylation state of Akt by modulating the ability of Akt to be dephosphorylated by PP2Ac during C2C12 myoblast differentiation [15].

Associations of PPP2CA with chemical compounds

• Previous studies have identified the free catalytic subunit of protein phosphatase 2A (PP2Ac) as the cellular phosphatase which can remove inhibitory phosphoryl groups from serines 120 and 123 [16].
• Yeast was employed as a novel system for mutagenesis and functional analysis of human PP2Ac, revealing that the invariant C-terminal leucine residue, a site of regulatory methylation, is apparently dispensable for protein function [17].
• Modification of the sphingoid chain also abolished the ability of ceramide to activate PP2Ac [18].
• In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered [19].
• Mannoheptulose, an inhibitor of glucose metabolism, completely prevented inhibitory effects of glucose on the CML of PP2Ac [20].
• Inhibition of PAK by overexpression of PP2Calpha or the kinase inhibitory domain prevented sorbitol-induced focal adhesion dissolution [21].

Other interactions of PPP2CA

• The mRNA level of PP2A beta was markedly decreased within 5 h after addition of ATRA, but there was only a slight increase in the mRNA level of PP2A alpha [22].
• The interactions of several candidate proteins, such as tuberous sclerosis complex 2, RhoB, R-Ras, and Nm23H2, with PP2Ac, were confirmed by in vitro binding analyses and/or coimmunoprecipitation experiments [23].
• When matched for activity toward glycogen phosphorylase, PP2A1 was five- to sevenfold more active than PP2A2 and 35-fold to 70-fold more active than the free catalytic subunit (PP2Ac) toward the three CDK-labeled substrates [24].
• Whole-cell treatments with okadaic acid or calyculin A diminished SERT/PP2Ac associations [25].
• Both biochemical fractionation and immunofluorescence analysis of detergent-extracted cells revealed that fractions of PP2Ac, PR65, and B55 were tightly associated with vimentin [26].

Analytical, diagnostic and therapeutic context of PPP2CA

• To understand the complex signaling networking associated with PP2A, we searched proteins interacting with the catalytic subunit of protein phosphatase 2A (PP2Ac) by a pull-down analysis followed by 2-D gel electrophoresis and proteomic analyses [23].
• Furthermore, binding of inhibitors to PP2Ac and/or PP1c in MCF7 cells led to differential posttranslational modifications of the carboxyl termini of the proteins as demonstrated by Western blotting [27].
• Protein-protein interaction between bestrophin and PP2Ac and the structural subunit of PP2A, PR65, was confirmed by reciprocal immunoprecipitation [28].
• The effectiveness of a rural regionalized perinatal care (RPC) program was evaluated by a controlled, population-based design [29].
• BACKGROUND: This prospective cohort study assessed the cost-effectiveness of treating 30 women with postnatal depression (PND) at a specialised psychiatric Parent and Baby Day Unit (PBDU), compared to 30 women treated using routine primary care (RPC) [30].

References