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PPP3CA  -  protein phosphatase 3, catalytic subunit,...

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Disease relevance of PPP3CA

  • Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy [1].
  • Agonist-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. & Snyder, S. H. (1998) J. Biol. Chem. 273, 18325-18331] [1].
  • Partial digestion of the hybrid protein with Staphylococcus aureus V-8 protease produced several immunoreactive peptides that appeared identical to fragments generated from authentic brain calcineurin [2].
  • Calcineurin A was purified by calmodulin-Sepharose affinity chromatography from Sf9 cells infected with recombinant baculovirus containing the cDNA of a rat calcineurin A isoform [3].
  • Our results suggest that cyclosporin A-induced hypertension may involve, at least in part, the attenuation of endothelium-derived NO production through a calcineurin-sensitive pathway regulating eNOS dephosphorylation [4].

Psychiatry related information on PPP3CA


High impact information on PPP3CA


Chemical compound and disease context of PPP3CA


Biological context of PPP3CA


Anatomical context of PPP3CA


Associations of PPP3CA with chemical compounds

  • The immunosuppressive action of cyclosporin A is believed to result from binding of the drug to cyclophilins (intracellular peptidyl-prolyl cis-trans isomerases), and inhibition of the protein phosphatase calcineurin by the cyclosporin A-cyclophilin complex [10].
  • Calcineurin (CN) is a Ca(2+)/calmodulin(CaM)-dependent serine/threonine protein phosphatase which is a heterodimer composed of a 61 kDa catalytic subunit (CNA) and a 19 kDa regulatory subunit (CNB) [17].
  • Similar to other CyPs from mammalian cells, pCyP B, when complexed with CsA, inhibited the phosphatase activity of bovine calcineurin [18].
  • Calcineurin (CaN), a Ca2+/calmodulin-dependent serine/threonine phosphatase, has been shown to be inhibited by the complex of the immunosuppressant cyclosporin A (CsA) and its receptor, cyclophilin (CyP), but not by either alone [19].
  • [3H]FK506-FK506-binding protein (FKBP) complex does not bind polyethyleneimine-treated glass fiber filters, on the other hand, it binds the filter when it makes a complex with calcineurin [20].

Physical interactions of PPP3CA


Enzymatic interactions of PPP3CA

  • The peptide map analysis revealed that calcineurin dephosphorylated MAP2 and tau factor universally, but not in a site-specific manner [22].
  • DARPP-32 phosphorylated on Thr-34 by cAMP-dependent protein kinase is a potent inhibitor of protein phosphatase 1 and an excellent substrate for calcineurin, a Ca2+/calmodulin-dependent protein phosphatase [23].
  • Calcineurin purified from bovine brain is shown to possess phosphotyrosyl -protein phosphatase activity towards proteins phosphorylated by the epidermal growth factor receptor/kinase [24].
  • Calcineurin (CN) dephosphorylated [32P] phosphotyrosyl glutamine synthetase, a model phosphoprotein substrate containing approximately 1 mol of phosphotyrosine per mol subunit [25].

Regulatory relationships of PPP3CA

  • FK506 and FKBP-12 inhibited calcineurin in a concentration-dependent manner, and complete inhibition of the phosphatase activity appeared to require a molar excess of FKBP12-FK506 complex [11].
  • Escherichia coli expressed cardiac Hsp70 stimulated a 2-fold increase in calcineurin (CaN) activity [26].
  • Here we provide evidence, using both purified proteins and brain slices, that phosphorylation of DARPP-32 on Ser-137 by casein kinase I inhibits the dephosphorylation of Thr-34 by calcineurin [23].
  • The Ca(2+)- and calmodulin-dependent protein phosphatase calcineurin is inhibited by the immunosuppressant drug cyclosporin A in the presence of cyclophilin A or B [27].
  • A calcium-initiated signaling pathway propagated through calcineurin and cAMP response element-binding protein activates proenkephalin gene transcription after depolarization [28].

Other interactions of PPP3CA


Analytical, diagnostic and therapeutic context of PPP3CA

  • Immunochemical measurements revealed tissue differences in the concentration of calcineurin, which may be of importance to the selectivity for immunosuppression of all of the biological effects [11].
  • The solution conformations of both recombinant enzyme and bovine calcineurin were assayed under the same conditions using intrinsic fluorescence spectroscopy and circular dichroism spectropolarimetry, and results showed their graphs are approximately identical [17].
  • Purified calcineurin was subjected to one- and two-dimensional gel electrophoresis and protein blotting; as expected, only the 61-kDa calmodulin-binding subunit was detected [30].
  • When purified bovine brain calcineurin, a calmodulin-dependent protein phosphatase, was immobilized on nitrocellulose slot blots, biotinylated calmodulin bound in a calcium-dependent saturable manner; these blots were then quantified by densitometry [30].
  • Incubation of the protein with 63Ni2+ (or 54Mn2+) followed by gel filtration to separate free and protein-bound ions indicated that calcineurin could maximally bind 2 mol/mol of Ni2+ or Mn2+ [31].


  1. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Taigen, T., De Windt, L.J., Lim, H.W., Molkentin, J.D. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  2. Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin. Kincaid, R.L., Nightingale, M.S., Martin, B.M. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  3. Characterization of the phosphatase activity of a baculovirus-expressed calcineurin A isoform. Perrino, B.A., Fong, Y.L., Brickey, D.A., Saitoh, Y., Ushio, Y., Fukunaga, K., Miyamoto, E., Soderling, T.R. J. Biol. Chem. (1992) [Pubmed]
  4. Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. Kou, R., Greif, D., Michel, T. J. Biol. Chem. (2002) [Pubmed]
  5. The Caenorhabditis elegans homologue of Down syndrome critical region 1, RCN-1, inhibits multiple functions of the phosphatase calcineurin. Lee, J.I., Dhakal, B.K., Lee, J., Bandyopadhyay, J., Jeong, S.Y., Eom, S.H., Kim, d.o. .H., Ahnn, J. J. Mol. Biol. (2003) [Pubmed]
  6. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Griffith, J.P., Kim, J.L., Kim, E.E., Sintchak, M.D., Thomson, J.A., Fitzgibbon, M.J., Fleming, M.A., Caron, P.R., Hsiao, K., Navia, M.A. Cell (1995) [Pubmed]
  7. Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin. Chang, H.Y., Takei, K., Sydor, A.M., Born, T., Rusnak, F., Jay, D.G. Nature (1995) [Pubmed]
  8. Localization of calcineurin in the mature and developing retina. Nakazawa, A., Usuda, N., Matsui, T., Hanai, T., Matsushita, S., Arai, H., Sasaki, H., Higuchi, S. J. Histochem. Cytochem. (2001) [Pubmed]
  9. Response of recombinant calcineurin to metal ions, reduction-oxidation agents, and enzymatic modification. Rhode, D.J., Imparl-Radosevich, J., Bartleson, C., Spannaus-Martin, D.J., Martin, B.L. Protein Expr. Purif. (2002) [Pubmed]
  10. Roles of peptidyl-prolyl cis-trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin. Bell, A., Wernli, B., Franklin, R.M. Biochem. Pharmacol. (1994) [Pubmed]
  11. FKBP12-FK506 complex inhibits phosphatase activity of two mammalian isoforms of calcineurin irrespective of their substrates or activation mechanisms. Mukai, H., Kuno, T., Chang, C.D., Lane, B., Luly, J.R., Tanaka, C. J. Biochem. (1993) [Pubmed]
  12. Molecular cloning, expression, purification and characterization of calcineurin from bovine cardiac muscle. Selvakumar, P., Lakshmikuttyamma, A., Anderson, D.H., Sharma, R.K. Biochimie (2005) [Pubmed]
  13. FK506 inhibits Cl- secretion in airway epithelium via calcineurin-independent mechanism. Kanoh, S., Kondo, M., Tamaoki, J., Kobayashi, H., Motoyoshi, K., Nagai, A. Eur. J. Pharmacol. (2001) [Pubmed]
  14. Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain. Guerini, D., Klee, C.B. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  15. Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. Baukal, A.J., Hunyady, L., Catt, K.J., Balla, T. J. Biol. Chem. (1994) [Pubmed]
  16. The sites at which brain microtubule-associated protein 2 is phosphorylated in vivo differ from those accessible to cAMP-dependent kinase in vitro. Murthy, A.S., Bramblett, G.T., Flavin, M. J. Biol. Chem. (1985) [Pubmed]
  17. Function and structure of recombinant single chain calcineurin. Qin, Y.L., Yu, D.Y., Wei, Q. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  18. pCyP B: a chloroplast-localized, heat shock-responsive cyclophilin from fava bean. Luan, S., Lane, W.S., Schreiber, S.L. Plant Cell (1994) [Pubmed]
  19. Specific interaction of the cyclophilin-cyclosporin complex with the B subunit of calcineurin. Li, W., Handschumacher, R.E. J. Biol. Chem. (1993) [Pubmed]
  20. Detection of the FK506-FKBP-calcineurin complex by a simple binding assay. Asami, M., Kuno, T., Mukai, H., Tanaka, C. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  21. Binding of active cyclosporins to cyclophilin A and B, complex formation with calcineurin A. Ryffel, B., Woerly, G., Murray, M., Eugster, H.P., Car, B. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  22. Dephosphorylation of microtubule-associated protein 2, tau factor, and tubulin by calcineurin. Goto, S., Yamamoto, H., Fukunaga, K., Iwasa, T., Matsukado, Y., Miyamoto, E. J. Neurochem. (1985) [Pubmed]
  23. Dopamine- and cAMP-regulated phosphoprotein DARPP-32: phosphorylation of Ser-137 by casein kinase I inhibits dephosphorylation of Thr-34 by calcineurin. Desdouits, F., Siciliano, J.C., Greengard, P., Girault, J.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  24. Characterization of phosphotyrosyl-protein phosphatase activity associated with calcineurin. Chernoff, J., Sells, M.A., Li, H.C. Biochem. Biophys. Res. Commun. (1984) [Pubmed]
  25. Modulation of calcineurin phosphotyrosyl protein phosphatase activity by calmodulin and protease treatment. Kincaid, R.L., Martensen, T.M., Vaughan, M. Biochem. Biophys. Res. Commun. (1986) [Pubmed]
  26. Molecular cloning of bovine cardiac muscle heat-shock protein 70 kDa and its phosphorylation by cAMP-dependent protein kinase in vitro. Lakshmikuttyamma, A., Selvakumar, P., Anderson, D.H., Datla, R.S., Sharma, R.K. Biochemistry (2004) [Pubmed]
  27. Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Swanson, S.K., Born, T., Zydowsky, L.D., Cho, H., Chang, H.Y., Walsh, C.T., Rusnak, F. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  28. A calcium-initiated signaling pathway propagated through calcineurin and cAMP response element-binding protein activates proenkephalin gene transcription after depolarization. Hahm, S.H., Chen, Y., Vinson, C., Eiden, L.E. Mol. Pharmacol. (2003) [Pubmed]
  29. Pituitary adenylate cyclase-activating polypeptide regulation of vasoactive intestinal polypeptide transcription requires Ca2+ influx and activation of the serine/threonine phosphatase calcineurin. Lee, H.W., Hahm, S.H., Hsu, C.M., Eiden, L.E. J. Neurochem. (1999) [Pubmed]
  30. A rapid and sensitive method for detection and quantification of calcineurin and calmodulin-binding proteins using biotinylated calmodulin. Billingsley, M.L., Pennypacker, K.R., Hoover, C.G., Brigati, D.J., Kincaid, R.L. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  31. Stoichiometry and dynamic interaction of metal ion activators with calcineurin phosphatase. Pallen, C.J., Wang, J.H. J. Biol. Chem. (1986) [Pubmed]
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