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Gene Review

Ppp2r1a  -  protein phosphatase 2, regulatory subunit...

Mus musculus

Synonyms: 6330556D22Rik, PP2A, PP2A subunit A isoform PR65-alpha, PP2A subunit A isoform R1-alpha, PR65, ...
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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


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


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


  1. Overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function. Gergs, U., Boknik, P., Buchwalow, I., Fabritz, L., Matus, M., Justus, I., Hanske, G., Schmitz, W., Neumann, J. J. Biol. Chem. (2004) [Pubmed]
  2. A truncated isoform of the PP2A B56gamma regulatory subunit reduces irradiation-induced Mdm2 phosphorylation and could contribute to metastatic melanoma cell radioresistance. Koma, Y.I., Ito, A., Watabe, K., Kimura, S.H., Kitamura, Y. Histol. Histopathol. (2004) [Pubmed]
  3. HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. Kawabe, T., Muslin, A.J., Korsmeyer, S.J. Nature (1997) [Pubmed]
  4. Expression of a peptide inhibitor of protein phosphatase 1 increases phosphorylation and activity of CREB in NIH 3T3 fibroblasts. Alberts, A.S., Montminy, M., Shenolikar, S., Feramisco, J.R. Mol. Cell. Biol. (1994) [Pubmed]
  5. Loss of microglial ramification in microglia-astrocyte cocultures: involvement of adenylate cyclase, calcium, phosphatase, and Gi-protein systems. Kalla, R., Bohatschek, M., Kloss, C.U., Krol, J., Von Maltzan, X., Raivich, G. Glia (2003) [Pubmed]
  6. Altered phosphorylation of cytoskeletal proteins in mutant protein phosphatase 2A transgenic mice. Schild, A., Ittner, L.M., Götz, J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  7. Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A. Pallas, D.C., Shahrik, L.K., Martin, B.L., Jaspers, S., Miller, T.B., Brautigan, D.L., Roberts, T.M. Cell (1990) [Pubmed]
  8. A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Fellner, T., Lackner, D.H., Hombauer, H., Piribauer, P., Mudrak, I., Zaragoza, K., Juno, C., Ogris, E. Genes Dev. (2003) [Pubmed]
  9. Endothall thioanhydride inhibits protein phosphatases-1 and -2A in vivo. Erdödi, F., Tóth, B., Hirano, K., Hirano, M., Hartshorne, D.J., Gergely, P. Am. J. Physiol. (1995) [Pubmed]
  10. Effect of melatonin on the oxidative stress in N1E-115 cells is not mediated by mt1 receptors. Montilla, P., Feijóo, M., Muñoz, M.C., Muñoz-Castañeda, J.R., Bujalance, I., Túnez, I. Journal of physiology and biochemistry. (2003) [Pubmed]
  11. Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. Chiang, C.W., Kanies, C., Kim, K.W., Fang, W.B., Parkhurst, C., Xie, M., Henry, T., Yang, E. Mol. Cell. Biol. (2003) [Pubmed]
  12. Protein phosphatase 2A regulates apoptosis in intestinal epithelial cells. Ray, R.M., Bhattacharya, S., Johnson, L.R. J. Biol. Chem. (2005) [Pubmed]
  13. Impaired development of the Harderian gland in mutant protein phosphatase 2A transgenic mice. Schild, A., Isenmann, S., Tanimoto, N., Tonagel, F., Seeliger, M.W., Ittner, L.M., Kretz, A., Ogris, E., Götz, J. Mech. Dev. (2006) [Pubmed]
  14. Transgenic expression of protein phosphatase 2A regulatory subunit B56gamma disrupts distal lung differentiation. Everett, A.D., Kamibayashi, C., Brautigan, D.L. Am. J. Physiol. Lung Cell Mol. Physiol. (2002) [Pubmed]
  15. Interaction of nucleoredoxin with protein phosphatase 2A. Lechward, K., Sugajska, E., de Baere, I., Goris, J., Hemmings, B.A., Zolnierowicz, S. FEBS Lett. (2006) [Pubmed]
  16. Increase in potential activities of protein phosphatases PP1 and PP2A in lymphoid tissues of autoimmune MRL/MpJ-lpr/lpr mice. Matsuzawa, S., Tamura, T., Mizuno, Y., Kobayashi, S., Okuyama, H., Tsukitani, Y., Uemura, D., Kikuchi, K. J. Biochem. (1992) [Pubmed]
  17. Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes. Ugi, S., Imamura, T., Maegawa, H., Egawa, K., Yoshizaki, T., Shi, K., Obata, T., Ebina, Y., Kashiwagi, A., Olefsky, J.M. Mol. Cell. Biol. (2004) [Pubmed]
  18. Positive regulation of IkappaB kinase signaling by protein serine/threonine phosphatase 2A. Kray, A.E., Carter, R.S., Pennington, K.N., Gomez, R.J., Sanders, L.E., Llanes, J.M., Khan, W.N., Ballard, D.W., Wadzinski, B.E. J. Biol. Chem. (2005) [Pubmed]
  19. Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. Baroja, M.L., Vijayakrishnan, L., Bettelli, E., Darlington, P.J., Chau, T.A., Ling, V., Collins, M., Carreno, B.M., Madrenas, J., Kuchroo, V.K. J. Immunol. (2002) [Pubmed]
  20. Insulin-like growth factor I controls a mutually exclusive association of RACK1 with protein phosphatase 2A and beta1 integrin to promote cell migration. Kiely, P.A., O'Gorman, D., Luong, K., Ron, D., O'Connor, R. Mol. Cell. Biol. (2006) [Pubmed]
  21. Okadaic acid suppresses neural differentiation-dependent expression of the neurofilament-L gene in P19 embryonal carcinoma cells by post-transcriptional modification. Sasahara, Y., Kobayashi, T., Onodera, H., Onoda, M., Ohnishi, M., Kato, S., Kusuda, K., Shima, H., Nagao, M., Abe, H., Yanagawa, Y., Hiraga, A., Tamura, S. J. Biol. Chem. (1996) [Pubmed]
  22. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Yeh, E., Cunningham, M., Arnold, H., Chasse, D., Monteith, T., Ivaldi, G., Hahn, W.C., Stukenberg, P.T., Shenolikar, S., Uchida, T., Counter, C.M., Nevins, J.R., Means, A.R., Sears, R. Nat. Cell Biol. (2004) [Pubmed]
  23. A-type lamins are essential for TGF-beta1 induced PP2A to dephosphorylate transcription factors. Van Berlo, J.H., Voncken, J.W., Kubben, N., Broers, J.L., Duisters, R., van Leeuwen, R.E., Crijns, H.J., Ramaekers, F.C., Hutchison, C.J., Pinto, Y.M. Hum. Mol. Genet. (2005) [Pubmed]
  24. Cytostatin, an inhibitor of cell adhesion to extracellular matrix, selectively inhibits protein phosphatase 2A. Kawada, M., Amemiya, M., Ishizuka, M., Takeuchi, T. Biochim. Biophys. Acta (1999) [Pubmed]
  25. Characterization of protein phosphatases in mouse oocytes. Smith, G.D., Sadhu, A., Mathies, S., Wolf, D.P. Dev. Biol. (1998) [Pubmed]
  26. Distinct role of protein phosphatase 2A subunit Calpha in the regulation of E-cadherin and beta-catenin during development. Götz, J., Probst, A., Mistl, C., Nitsch, R.M., Ehler, E. Mech. Dev. (2000) [Pubmed]
  27. Immunohistochemical localization of microcystin-LR in the liver of mice: a study on the pathogenesis of microcystin-LR-induced hepatotoxicity. Yoshida, T., Makita, Y., Tsutsumi, T., Nagata, S., Tashiro, F., Yoshida, F., Sekijima, M., Tamura, S., Harada, T., Maita, K., Ueno, Y. Toxicologic pathology. (1998) [Pubmed]
  28. Proteomics approach on microcystin binding proteins in mouse liver for investigation of microcystin toxicity. Imanishi, S., Harada, K. Toxicon (2004) [Pubmed]
  29. Alterations in activities of protein phosphatases PP1 and PP2A in T and B lymphocytes of autoimmune MRL/MpJ-lpr/lpr mice. Zhu, T., Matsuzawa, S., Mizuno, Y., Kikuchi, K. J. Biochem. (1993) [Pubmed]
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