Disease relevance of Ppp2r1a

• Taken together, these findings are indicative of the fundamental role of PP2A in cardiac function and imply that disturbances in protein phosphatases expression and activity may cause or aggravate the course of cardiac diseases [1].
• Defects, such as deltagamma1, in PP2A may thus contribute to melanoma cell radioresistance [2].
• Thus HOX11 is a cellular oncogene that targets PP2A and PP1, both of which are targets for oncogenic viruses and chemical tumour promoters [3].
• In contrast, injection of a plasmid encoding simian virus 40 small t antigen, which interacts with PP2A to inhibit its activity towards several phosphoprotein substrates, had no effect on the phosphorylation state of CREB in stimulated or unstimulated NIH 3T3 cells [4].
• Okadaic acid (70 nM), the inhibitor of protein phosphatases 1 and 2A (PP1/PP2A), and pertussis toxin (12.5 microg/ml), a G(i)-protein inhibitor, also showed similar effects [5].

Psychiatry related information on Ppp2r1a

• Protein phosphatase 2A (PP2A) is a family of heterotrimeric enzymes with diverse functions under physiologic and pathologic conditions such as Alzheimer's disease [6].

High impact information on Ppp2r1a

• Microsequencing of the 36 kd protein indicated that it was probably identical to the catalytic subunit of protein phosphatase 2A (PP2A) [7].
• Inhibition of PP2A can regulate the cell cycle and control the activation of maturation-promoting factor in Xenopus oocytes [3].
• Protein phosphatase 2A (PP2A) is an essential intracellular serine/threonine phosphatase containing a catalytic subunit that possesses the potential to dephosphorylate promiscuously tyrosine-phosphorylated substrates in vitro [8].
• Here we report a novel and phylogenetically conserved mechanism to generate active phospho-serine/threonine-specific PP2A in vivo [8].
• Deletion of the yeast PTPA homologs generated a PP2A catalytic subunit with a conformation different from the wild-type enzyme, as indicated by its altered substrate specificity, reduced protein stability, and metal dependence [8].

Chemical compound and disease context of Ppp2r1a

• The objective of this study was to relate the toxicity of several cantharidin-derivative pesticides with their abilities to inhibit protein phosphatases-1 (PP1) and -2A (PP2A) [9].
• The potency sequence of ETA > CA > endothall was established for the inhibition of PP1 and PP2A in vivo and shows close correlation with the sequence of relative toxicity [9].
• To explore if protective effect of melatonin on oxidative stress induced by okadaic acid, an inhibitor of protein phosphatases PP1 and PP2A, is mediated by membrane receptors subtype mt1, we used an in vitro model with N1E-115 neuroblastoma cells [10].

Biological context of Ppp2r1a

• Phosphotyrosyl phosphatase activator (PTPA), a protein of so far unknown intracellular function, is required for the biogenesis of active and specific PP2A [8].
• Thus, PP2A dephosphorylation of pSer112 is the key initiating event regulating the activation of BAD during interleukin-3 withdrawal-induced apoptosis [11].
• Inhibition of PP2A in cells depleted of polyamines correlated well with increased phosphorylation of Bad at Ser112 [12].
• Moreover, our data demonstrate that PP2A subunit composition plays a crucial role in regulating cell adhesion and as a consequence in the development of the Harderian gland [13].
• To determine why expression of the L309A mutant caused this phenotype, we determined the PP2A subunit composition [13].

Anatomical context of Ppp2r1a

• This was accompanied by a significant increase of PP2A enzyme activity in the myocardium [1].
• The distal epithelium of the developing lung exhibits high-level expression of protein phosphatase 2A (PP2A), a vital signaling enzyme [14].
• 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 [15].
• The differential assay conditions for protein phosphatases PP1, PP2A, and PP2C were extensively studied by using crude extracts from mouse lymphoid tissues as enzyme sources [16].
• In support of this result, when inhibitory anti-PP2A antibody was microinjected into 3T3-L1 adipocytes, we found a twofold increase in GLUT4 translocation in the absence of insulin [17].

Associations of Ppp2r1a with chemical compounds

• How PP2A acquires its intracellular specificity and activity for serine/threonine-phosphorylated substrates is unknown [8].
• First, TNF-induced degradation of IkappaB is attenuated in cells treated with okadaic acid or fostriecin, two potent inhibitors of PP2A [18].
• Our data imply that the lysine-rich motif in CTLA-4 may be used to identify small molecules that block its binding to PP2A and act as agonists for CTLA-4 function [19].
• PP2A substrate specificity is determined by regulatory subunits with leucine 309 of the catalytic subunit playing a crucial role in the recruitment of regulatory subunits into the complex in vitro [13].
• This suggests that integrin ligation displaces PP2A from RACK1 [20].

Physical interactions of Ppp2r1a

• Second, PP2A forms stable complexes with IKK in untransfected mammalian cells [18].
• These results demonstrate that the OA treatment inhibits the differentiation-dependent increase in NF-L gene expression by destabilizing its mRNAs and suggest that PP2A plays key roles in the differentiation-dependent enhanced expression of the NF-L gene and is the point of the action of OA [21].
• Furthermore, the absence of Pin1 or inhibition of PP2A stabilizes c-Myc [22].

Enzymatic interactions of Ppp2r1a

• Recently, B56gamma subunit-containing PP2A holoenzymes have shown to dephosphorylate Mdm2, a negative regulator of p53 [2].
• TGF-beta1 dephosphorylated pRB through PP2A, both of which, we show, are associated with lamin A/C [23].

Regulatory relationships of Ppp2r1a

• A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance [2].
• A-type lamins are essential for TGF-beta1 induced PP2A to dephosphorylate transcription factors [23].
• These results indicate that cytostatin inhibits cell adhesion through modification of focal contact proteins such as paxillin by inhibiting a PP2A type protein serine/threonine phosphatase [24].

Other interactions of Ppp2r1a

• Here we provided several in vivo lines of evidence indicating that PP2A plays a positive rather than a negative role in the regulation of IKK [18].
• Inhibition of PP2A by okadaic acid and fostriecin or PP2A small interfering RNA transfection significantly decreased TNF-alpha-induced apoptosis in control and polyamine-depleted cells [12].
• We propose that B56gamma is expressed at a particular stage of lung development to modulate PP2A action on the Wnt/beta-catenin signaling pathway during lung airway morphogenesis [14].
• To address this issue, we generated transgenic mice that overexpress the catalytic subunit alpha of protein phosphatase 2A (PP2A) (PP2Acalpha) in the heart driven by the alpha-myosin heavy chain promoter [1].
• PP2A competed with 14-3-3 for BAD binding, and survival factor withdrawal enhanced PP2A association with BAD [11].

Analytical, diagnostic and therapeutic context of Ppp2r1a

• At the protein level only PP1alpha and PP2A were recognized in fully grown GVI oocytes by Western blot analysis [25].
• Inactivation of the gene encoding the PP2A catalytic subunit Calpha by gene targeting generates a lethal embryonic phenotype [26].
• Immunoblotting and high-performance liquid chromatography analyses of liver extracts were also performed to determine the binding form of MCLR to PP1 and PP2A (MCLR-PP1/PP2A adducts) and free MCLR [27].
• A systematic process of MC affinity chromatography and proteomics, using two-dimensional gel electrophoresis and MALDI-TOFMS, indicated the existence of some MC-binding proteins including the complexes of PP1, PP2A, and PP4 with their own regulatory subunits in mouse liver extracts [28].
• Spontaneous PP2A activity showed similar levels in T and B lymphocytes from normal mice, but potential PP2A activity, which was measured after treatment with 2-mercaptoethanol, was significantly higher in T lymphocytes from MRL/lpr mice than those from controls [29].

References