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Gene Review

PPP4C  -  protein phosphatase 4, catalytic subunit

Homo sapiens

Synonyms: PP-X, PP4, PP4C, PPH3, PPP4, ...
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Disease relevance of PPP4C


High impact information on PPP4C


Chemical compound and disease context of PPP4C

  • Unbound plasma concentrations of ropivacaine and PPX remained well below threshold levels for systemic central nervous toxicity [8].
  • We have investigated the regulation of the JNK-1 kinase by co-transfecting phosphatases PP4 and M3/6 in prostate cancer cell lines PC-3 and LNCaP, which have been previously stimulated with human EGF or cisplatin [9].
  • A dehydrobutyrine (Dhb)-containing microcystin variant [Asp3, ADMAdda5, Dhb7]microcystin-HtyR isolated from Nostoc sp. was found to potently inhibit PP1, PP2A, PPP4 and PPP5 with IC50 values similar to those of microcystin-LR [10].

Biological context of PPP4C

  • Assignment of the human serine/threonine protein phosphatase 4 gene (PPP4C) to chromosome 16p11-p12 by fluorescence in situ hybridization [11].
  • The final product contained two major proteins: the PP4 catalytic subunit plus a protein that migrated as a doublet of 120-125 kDa on SDS-polyacrylamide gel electrophoresis [12].
  • Coprecipitated complex kinase assay revealed a fragment of NF-kappaB p65 (amino acids 279-444) to contain potential phosphorylation sites that directly interact with PP4 [13].
  • The deduced amino acid sequence of human PPX differs from that of rabbit PPX in only two in 307 amino acids, demonstrating that the structure of PPX has been highly conserved during the course of mammalian evolution [2].
  • PP4 is also inhibited in the nanomolar range by several naturally occurring tumour promoters and toxins, with similar IC50 values to those obtained for PP2A [14].

Anatomical context of PPP4C

  • As a first step toward characterization of PP4 holoenzymes and identification of putative PP4 regulatory subunits, PP4 was purified from bovine testis soluble extracts [12].
  • These showed that although PPX was distributed throughout the cytoplasm and the nucleus, intense staining occurred at centrosomes [1].
  • Furthermore, tritiated PPX/C was immunoprecipitated from COS cell extracts incubated with the methyl donor S-adenosyl-l-[methyl-3H]methionine [15].
  • In addition, immunoblots of subcellular fractions and immunocytochemical analyses of rat brain sections demonstrated that PPX/C is predominantly localized to the nucleus, whereas PP2A/C is largely cytoplasmic [15].
  • PP2A but not PP4 inhibited 17,20 lyase activity in microsomes from cultured cells, but neither affected 17 alpha-hydroxylation [16].

Associations of PPP4C with chemical compounds

  • We found that PP4 interacted with HPK1 and that the proline-rich region of HPK1 was necessary and sufficient for this interaction [7].
  • PP4-overexpressing cells showed a decrease in Thr phosphorylation of NF-kappaB p65 to nearly undetectable levels, and both basal and cisplatin-induced NF-kappaB activities were higher than those in parental cells [13].
  • Thus the increase in immunoreactivity probably results from removal of a carboxymethyl group from PPX/C, as has been shown previously for PP2A/C [Favre, Zolnierowicz, Turowski and Hemmings (1994) J. Biol. Chem. 269, 16311-16317] [15].
  • Treating human adrenal NCI-H295A cells with the phosphatase inhibitors okadaic acid, fostriecin, and cantharidin increased 17,20 lyase activity, suggesting involvement of protein phosphatase 2A (PP2A) or 4 (PP4) [16].
  • Rifampin considerably increases the metabolism of ropivacaine to PPX and decreases the metabolism to 3-OH-ropivacaine in both nonsmokers and smokers [17].

Physical interactions of PPP4C

  • The PP4R1 cDNA clone engineered with an N-terminal Myc tag was expressed in COS M6 cells and PP4C co-immunoprecipitated with Myc-tagged PP4R1 [12].

Other interactions of PPP4C

  • Pulse-chase analysis showed that PP4 increased the half-life of HPK1 [7].
  • Mass spectrometry analysis of the purified complex revealed two major peaks, at 35 (PP4C) and 105 kDa (PP4R1) [12].
  • The encoded putative PPP4 regulatory subunit (termed PPP4R2), comprising 453 amino acids, had a molecular mass of 50.4 kDa [18].
  • Treatment of HEK293T cells with TNF-alpha resulted in time-dependent activation of endogenous PP4, peaking at 10 min, as well as increased serine and threonine phosphorylation of PP4 [19].

Analytical, diagnostic and therapeutic context of PPP4C

  • PP4 existed in two complexes of approximately 270-300 and 400-450 kDa as determined by gel filtration chromatography [12].
  • The intracellular localization of PPX was investigated by immunofluorescence using two different antibodies raised against bacterially expressed PPX and a PPX-specific peptide [1].
  • The plasma and urine samples were analyzed for unchanged ropivacaine and for four of its metabolites, i.e. 3-OH-2',6'-pipecoloxylidide (3-OH-PPX), 4-OH-ropivacaine, 3-OH-ropivacaine, and the N-dealkylated metabolite PPX, using GC and HPLC methods [20].
  • The enantiomers of ropivacaine and two of the major metabolites, 3-hydroxy-ropivacaine and 2',6'-pipecoloxylidide (PPX), were determined in urine samples by liquid chromatography on a Chiral AGP column after liquid-liquid extraction [21].
  • When compared with the negative pelvic X-ray group (NPX), the PPX group had a significantly higher mean Injury Severity Score, 24-hour mean requirement for blood and component therapy, and higher incidence of associated injury of chest and abdomen [22].


  1. 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]
  2. Protein phosphatase X has been highly conserved during mammalian evolution. Brewis, N.D., Cohen, P.T. Biochim. Biophys. Acta (1992) [Pubmed]
  3. The bvg-dependent promoters show similar behaviour in different Bordetella species and share sequence homologies. Scarlato, V., Prugnola, A., Aricò, B., Rappuoli, R. Mol. Microbiol. (1991) [Pubmed]
  4. A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules. Boddy, A.V., Plummer, E.R., Todd, R., Sludden, J., Griffin, M., Robson, L., Cassidy, J., Bissett, D., Bernareggi, A., Verrill, M.W., Calvert, A.H. Clin. Cancer Res. (2005) [Pubmed]
  5. Paclitaxel poliglumex (XYOTAX, CT-2103): a macromolecular taxane. Singer, J.W. Journal of controlled release : official journal of the Controlled Release Society. (2005) [Pubmed]
  6. Protein phosphatase 4 interacts with and down-regulates insulin receptor substrate 4 following tumor necrosis factor-alpha stimulation. Mihindukulasuriya, K.A., Zhou, G., Qin, J., Tan, T.H. J. Biol. Chem. (2004) [Pubmed]
  7. Protein phosphatase 4 is a positive regulator of hematopoietic progenitor kinase 1. Zhou, G., Boomer, J.S., Tan, T.H. J. Biol. Chem. (2004) [Pubmed]
  8. Continuous interscalene analgesia with ropivacaine 2 mg/ml after major shoulder surgery. Ekatodramis, G., Borgeat, A., Huledal, G., Jeppsson, L., Westman, L., Sjövall, J. Anesthesiology (2003) [Pubmed]
  9. Role of the phosphatase PP4 in the activation of JNK-1 in prostate carcinoma cell lines PC-3 and LNCaP resulting in increased AP-1 and EGR-1 activity. Inostroza, J., Sáenz, L., Calaf, G., Cabello, G., Parra, E. Biol. Res. (2005) [Pubmed]
  10. Inhibition of several protein phosphatases by a non-covalently interacting microcystin and a novel cyanobacterial peptide, nostocyclin. Hastie, C.J., Borthwick, E.B., Morrison, L.F., Codd, G.A., Cohen, P.T. Biochim. Biophys. Acta (2005) [Pubmed]
  11. Assignment of the human serine/threonine protein phosphatase 4 gene (PPP4C) to chromosome 16p11-p12 by fluorescence in situ hybridization. Bastians, H., Krebber, H., Hoheisel, J., Ohl, S., Lichter, P., Ponstingl, H., Joos, S. Genomics (1997) [Pubmed]
  12. Purification and identification of a novel subunit of protein serine/threonine phosphatase 4. Kloeker, S., Wadzinski, B.E. J. Biol. Chem. (1999) [Pubmed]
  13. Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation. Yeh, P.Y., Yeh, K.H., Chuang, S.E., Song, Y.C., Cheng, A.L. J. Biol. Chem. (2004) [Pubmed]
  14. Purification of protein phosphatase 4 catalytic subunit: inhibition by the antitumour drug fostriecin and other tumour suppressors and promoters. Hastie, C.J., Cohen, P.T. FEBS Lett. (1998) [Pubmed]
  15. Carboxymethylation of nuclear protein serine/threonine phosphatase X. Kloeker, S., Bryant, J.C., Strack, S., Colbran, R.J., Wadzinski, B.E. Biochem. J. (1997) [Pubmed]
  16. Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. Pandey, A.V., Mellon, S.H., Miller, W.L. J. Biol. Chem. (2003) [Pubmed]
  17. Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine. Jokinen, M.J., Olkkola, K.T., Ahonen, J., Neuvonen, P.J. Clin. Pharmacol. Ther. (2001) [Pubmed]
  18. A novel 50 kDa protein forms complexes with protein phosphatase 4 and is located at centrosomal microtubule organizing centres. Hastie, C.J., Carnegie, G.K., Morrice, N., Cohen, P.T. Biochem. J. (2000) [Pubmed]
  19. Protein phosphatase 4 is involved in tumor necrosis factor-alpha-induced activation of c-Jun N-terminal kinase. Zhou, G., Mihindukulasuriya, K.A., MacCorkle-Chosnek, R.A., Van Hooser, A., Hu, M.C., Brinkley, B.R., Tan, T.H. J. Biol. Chem. (2002) [Pubmed]
  20. Metabolism and excretion of ropivacaine in humans. Halldin, M.M., Bredberg, E., Angelin, B., Arvidsson, T., Askemark, Y., Elofsson, S., Widman, M. Drug Metab. Dispos. (1996) [Pubmed]
  21. Lack of metabolic racemisation of ropivacaine, determined by liquid chromatography using a chiral AGP column. Arvidsson, T., Bruce, H.F., Halldin, M.M. Chirality. (1995) [Pubmed]
  22. Utility of routine pelvic X-ray during blunt trauma resuscitation. Gillott, A., Rhodes, M., Lucke, J. The Journal of trauma. (1988) [Pubmed]
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