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Gene Review

PPP2R4  -  protein phosphatase 2A activator,...

Homo sapiens

Synonyms: PP2A, PP2A, subunit B', PR53 isoform, PR53, PTPA, Phosphotyrosyl phosphatase activator, ...
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Disease relevance of PPP2R4

  • We provide here biochemical and functional evidence demonstrating that human immunodeficiency virus type 1 (HIV-1) Vpr mediates G(2) arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25 [1].
  • Recent studies with DNA viruses have contributed to our understanding of critical tumor targets (such as EGFR, PP2A, Rb and p53) and have an impact on the development of novel therapies, including oncolytic viral agents, for the treatment of cancer [2].
  • Using baculovirus recombinants expressing individual PP2A subunits, we show that the dephosphorylation of furin in vitro requires heterotrimeric phosphatase containing B family regulatory subunits [3].
  • The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function [4].
  • Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome [5].

Psychiatry related information on PPP2R4

  • The activity of protein phosphatase-2A (PP2A) is compromised and is believed to be a cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain [6].
  • We have attempted to determine the effects of electroconvulsive shock (ECS) on protein phosphatase 2A (PP2A) in the frontal cortices of rats [7].

High impact information on PPP2R4

  • Because the only known targets of okadaic acid are the catalytic subunits PP1 and PP2A, these enzymes are crucial components of two basic functions carried out by cells: growth and division [8].
  • We show here that DNA-responsive checkpoints also activate PP2A/B56delta phosphatase complexes to dephosphorylate Cdc25 at a site distinct from Ser287 (T138), the phosphorylation of which is required for 14-3-3 release [9].
  • The serine/threonine phosphatase protein phosphatase 2A (PP2A) plays an essential role in many aspects of cellular functions and has been shown to be an important tumor suppressor [10].
  • Here we report the crystal structures of the PP2A core enzyme bound to two of its inhibitors, the tumor-inducing agents okadaic acid and microcystin-LR, at 2.6 and 2.8 A resolution, respectively [10].
  • Role for the PP2A/B56delta Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis [9].

Chemical compound and disease context of PPP2R4


Biological context of PPP2R4

  • Protein phosphatase 2A (PP2A) is a ubiquitously expressed member of the serine-threonine phosphatase family that is involved in regulation of many cellular processes including transcription, translation, cellular metabolism, and apoptosis [16].
  • Carboxymethylation affects PP2A activity and varies during the cell cycle [17].
  • Here, we report that substitution of glutamine for either of two putative active site histidines in the PP2A C subunit results in inactivation of PP2A and formation of stable complexes between PP2A and several cellular proteins [17].
  • ER promoter studies showed that regulation of ER through the PP2A pathway did not occur through transcriptional activation [16].
  • By testing OA for human cancer cell lines that express different types of ErbB receptors, we found that ErbB4 receptor expression was accompanied with positive regulation of PP2A for phosphorylation of Shc Tyr317 and its downstream ERK phosphorylation in MCF-7 and SK-OV-3 cell lines, but not in LNCaP and PC-3 cells [18].

Anatomical context of PPP2R4


Associations of PPP2R4 with chemical compounds


Physical interactions of PPP2R4


Enzymatic interactions of PPP2R4

  • Our data suggest that Vpr mediates G(2) arrest by enhancing the nuclear import of PP2A and by positively modulating its catalytic activity towards active phosphorylated nuclear cdc25 [1].

Co-localisations of PPP2R4

  • Notably, cyclin G2 colocalizes with both PP2A/C and B' subunits in detergent-resistant cellular compartments, suggesting that these complexes form in living cells [26].

Regulatory relationships of PPP2R4

  • Thus, PP2A regulates the ERK activity in a cell-specific manner, and it is speculated that distinct regulation of PP2A in the ErbB4 receptor signalling pathway may cause a difference in progression of cancer phenotypes [18].
  • These two genes may be part of the uncharacterized pathway for Vpr-induced G2 arrest in which Vpr upregulates PP2A to activate Wee1 and inhibit Cdc25 [28].

Other interactions of PPP2R4

  • Together, our findings suggest that cyclin G2-PP2A complexes inhibit cell cycle progression [26].
  • These data suggest a novel pathway controlling ER expression resulting from the activation of PP2A, potentially providing a novel therapeutic target [16].
  • Mutations of the PPP2R1B gene, which encodes the Abeta scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have been identified in several types of cancer including lung and breast carcinoma [4].
  • SCA12 is associated with an expansion of a CAG repeat in the 5' region of the gene PPP2R2B which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A [29].
  • However, PPX did not bind the 65 kDa regulatory subunit of PP2A [20].

Analytical, diagnostic and therapeutic context of PPP2R4


  1. Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A. Hrimech, M., Yao, X.J., Branton, P.E., Cohen, E.A. EMBO J. (2000) [Pubmed]
  2. DNA tumor viruses -- the spies who lyse us. O'Shea, C.C. Curr. Opin. Genet. Dev. (2005) [Pubmed]
  3. Regulation of endosome sorting by a specific PP2A isoform. Molloy, S.S., Thomas, L., Kamibayashi, C., Mumby, M.C., Thomas, G. J. Cell Biol. (1998) [Pubmed]
  4. The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Esplin, E.D., Ramos, P., Martinez, B., Tomlinson, G.E., Mumby, M.C., Evans, G.A. Genes Chromosomes Cancer (2006) [Pubmed]
  5. Adenovirus E4orf4 protein induces PP2A-dependent growth arrest in Saccharomyces cerevisiae and interacts with the anaphase-promoting complex/cyclosome. Kornitzer, D., Sharf, R., Kleinberger, T. J. Cell Biol. (2001) [Pubmed]
  6. Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease. Tanimukai, H., Grundke-Iqbal, I., Iqbal, K. Am. J. Pathol. (2005) [Pubmed]
  7. Transient activation of protein phosphatase 2A induced by electroconvulsive shock in the rat frontal cortex. Kang, U.G., Jeon, W.J., Kim, Y., Chung, C.K., Park, J.B., Juhnn, Y.S., Kim, Y.S. Neurosci. Lett. (2005) [Pubmed]
  8. Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Mumby, M.C., Walter, G. Physiol. Rev. (1993) [Pubmed]
  9. Role for the PP2A/B56delta Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis. Margolis, S.S., Perry, J.A., Forester, C.M., Nutt, L.K., Guo, Y., Jardim, M.J., Thomenius, M.J., Freel, C.D., Darbandi, R., Ahn, J.H., Arroyo, J.D., Wang, X.F., Shenolikar, S., Nairn, A.C., Dunphy, W.G., Hahn, W.C., Virshup, D.M., Kornbluth, S. Cell (2006) [Pubmed]
  10. Structure of Protein Phosphatase 2A Core Enzyme Bound to Tumor-Inducing Toxins. Xing, Y., Xu, Y., Chen, Y., Jeffrey, P.D., Chao, Y., Lin, Z., Li, Z., Strack, S., Stock, J.B., Shi, Y. Cell (2006) [Pubmed]
  11. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Li, L., Ren, C.H., Tahir, S.A., Ren, C., Thompson, T.C. Mol. Cell. Biol. (2003) [Pubmed]
  12. Simian virus 40 small tumor antigen inhibits dephosphorylation of protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Wheat, W.H., Roesler, W.J., Klemm, D.J. Mol. Cell. Biol. (1994) [Pubmed]
  13. Hepatocellular carcinoma cell lines from diethylnitrosamine phenobarbital-treated rats. Characterization and sensitivity to endothall, a protein serine/threonine phosphatase-2A inhibitor. Thièry, J.P., Blazsek, I., Legras, S., Marion, S., Reynes, M., Anjo, A., Adam, R., Misset, J.L. Hepatology (1999) [Pubmed]
  14. Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. Cicchillitti, L., Fasanaro, P., Biglioli, P., Capogrossi, M.C., Martelli, F. J. Biol. Chem. (2003) [Pubmed]
  15. Protein phosphatase 2A enhances activation of human immunodeficiency virus type 1 by phorbol myristate acetate. Faulkner, N.E., Lane, B.R., Bock, P.J., Markovitz, D.M. J. Virol. (2003) [Pubmed]
  16. Protein phosphatase 2A regulates estrogen receptor alpha (ER) expression through modulation of ER mRNA stability. Keen, J.C., Zhou, Q., Park, B.H., Pettit, C., Mack, K.M., Blair, B., Brenner, K., Davidson, N.E. J. Biol. Chem. (2005) [Pubmed]
  17. A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. Ogris, E., Du, X., Nelson, K.C., Mak, E.K., Yu, X.X., Lane, W.S., Pallas, D.C. J. Biol. Chem. (1999) [Pubmed]
  18. Expression of the ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway in human cancer cells. Yumoto, N., Yu, X., Hatakeyama, M. Mol. Cell. Biochem. (2006) [Pubmed]
  19. Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. Cayla, X., Van Hoof, C., Bosch, M., Waelkens, E., Vandekerckhove, J., Peeters, B., Merlevede, W., Goris, J. J. Biol. Chem. (1994) [Pubmed]
  20. PPX, a novel protein serine/threonine phosphatase localized to centrosomes. Brewis, N.D., Street, A.J., Prescott, A.R., Cohen, P.T. EMBO J. (1993) [Pubmed]
  21. Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest. Arachchige Don, A.S., Dallapiazza, R.F., Bennin, D.A., Brake, T., Cowan, C.E., Horne, M.C. Exp. Cell Res. (2006) [Pubmed]
  22. The {alpha}4 Regulatory Subunit Exerts Opposing Allosteric Effects on Protein Phosphatases PP6 and PP2A. Prickett, T.D., Brautigan, D.L. J. Biol. Chem. (2006) [Pubmed]
  23. Protein phosphatase 6 subunit with conserved Sit4-associated protein domain targets IkappaBepsilon. Stefansson, B., Brautigan, D.L. J. Biol. Chem. (2006) [Pubmed]
  24. Circulating cardiovascular disease risk factors and signaling in endothelial cell caveolae. Mineo, C., Shaul, P.W. Cardiovasc. Res. (2006) [Pubmed]
  25. Molecular cloning and mapping of the brain-abundant B1gamma subunit of protein phosphatase 2A, PPP2R2C, to human chromosome 4p16. Hu, P., Yu, L., Zhang, M., Zheng, L., Zhao, Y., Fu, Q., Zhao, S. Genomics (2000) [Pubmed]
  26. Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest. Bennin, D.A., Don, A.S., Brake, T., McKenzie, J.L., Rosenbaum, H., Ortiz, L., DePaoli-Roach, A.A., Horne, M.C. J. Biol. Chem. (2002) [Pubmed]
  27. Overexpression of the mTOR alpha4 phosphoprotein activates protein phosphatase 2A and increases Stat1alpha binding to PIAS1. Nien, W.L., Dauphinee, S.M., Moffat, L.D., Too, C.K. Mol. Cell. Endocrinol. (2007) [Pubmed]
  28. HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25. Elder, R.T., Yu, M., Chen, M., Zhu, X., Yanagida, M., Zhao, Y. Virology (2001) [Pubmed]
  29. SCA12: an unusual mutation leads to an unusual spinocerebellar ataxia. Holmes, S.E., Hearn, E.O., Ross, C.A., Margolis, R.L. Brain Res. Bull. (2001) [Pubmed]
  30. Structure and chromosomal localization of the human gene of the phosphotyrosyl phosphatase activator (PTPA) of protein phosphatase 2A. Van Hoof, C., Aly, M.S., Garcia, A., Cayla, X., Cassiman, J.J., Merlevede, W., Goris, J. Genomics (1995) [Pubmed]
  31. Identification and characterization of alternative splice products encoded by the human phosphotyrosyl phosphatase activator gene. Janssens, V., van Hoof, C., Martens, E., de Baere, I., Merlevede, W., Goris, J. Eur. J. Biochem. (2000) [Pubmed]
  32. Regional expression of protein phosphatase type 1 and 2A catalytic subunit isoforms in the human heart. Lüss, H., Klein-Wiele, O., Bokník, P., Herzig, S., Knapp, J., Linck, B., Müller, F.U., Scheld, H.H., Schmid, C., Schmitz, W., Neumann, J. J. Mol. Cell. Cardiol. (2000) [Pubmed]
  33. Differential distribution of protein phosphatase 2A in human breast carcinoma cell lines and its relation to estrogen receptor status. Gopalakrishna, R., Gundimeda, U., Fontana, J.A., Clarke, R. Cancer Lett. (1999) [Pubmed]
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