PP2B

• プロテインホスファターゼ2B

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calcineurin、protein phosphatase 2B

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/05 06:31:37」(JST)

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Crystallographic structure of calcineurin heterodimer composed of the catalytic (PPP3CA and regulatory (PPP3R1) subunits.

Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporine, pimecrolimus and tacrolimus.

Structure

Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca²⁺-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1, PPP3R2).

protein phosphatase 3, catalytic subunit, alpha isozyme Identifiers Symbol PPP3CA Alt. symbols CALN, CALNA Entrez 5530 HUGO 9314 OMIM 114105 RefSeq NM_000944 UniProt Q08209 Other data Locus Chr. 4 q24

protein phosphatase 3, catalytic subunit, beta isozyme Identifiers Symbol PPP3CB Alt. symbols CALNB Entrez 5532 HUGO 9315 OMIM 114106 RefSeq NM_021132 UniProt P16298 Other data Locus Chr. 10 q22.2

protein phosphatase 3, catalytic subunit, gamma isozyme Identifiers Symbol PPP3CC Entrez 5533 HUGO 9316 OMIM 114107 RefSeq NM_005605 UniProt P48454 Other data Locus Chr. 8 p21.3

protein phosphatase 3, regulatory subunit B, alpha Identifiers Symbol PPP3R1 Entrez 5534 HUGO 9317 OMIM 601302 RefSeq NM_000945 UniProt P63098 Other data Locus Chr. 2 p14

protein phosphatase 3, regulatory subunit B, beta Identifiers Symbol PPP3R2 Entrez 5535 HUGO 9318 OMIM 613821 RefSeq NM_147180 UniProt Q96LZ3 Other data Locus Chr. 9 q31

Mechanism of action

When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NFATs) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.

Clinical relevance

Rheumatic diseases

Adult rheumatoid arthritis (RA) as a single drug [1-5], or in combination with methotrexate [6,7]. The microemulsion formulation is approved by the Federal Drug Administration of the United States for treatment of severely active RA. Psoriatic arthritis [8,9] Psoriasis [10-12] Acute ocular Behçet’s disease [13] Juvenile idiopathic arthritis [14,15] Adult and juvenile polymyositis and dermatomyositis [14-21] Adult and juvenile systemic lupus erythematosus [22-25] Adult lupus membranous nephritis [26] Systemic sclerosis [27-29] Aplastic anemia [30,31] Steroid-resistant nephrotic syndrome (see "Treatment of minimal change disease in adults" and "Treatment of primary focal segmental glomerulosclerosis") Atopic dermatitis (see "Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)") Severe, corticosteroid-dependent asthma (see "Alternative and experimental agents for the treatment of asthma") Severe ulcerative colitis [32-34] Pemphigus vulgaris [35] Myasthenia gravis [36] Dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion) [37]

Schizophrenia

Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA. An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia.

Diabetes

Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells.

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.

Interactions

Calcineurin has been shown to interact with DSCR1 and AKAP5.

References

Further reading

• Cottrell JR, Levenson JM, Kim SH, Gibson HE, Richardson KA, Sivula M, Li B, Ashford CJ, Heindl KA, Babcock RJ, Rose DM, Hempel CM, Wiig KA, Laeng P, Levin ME, Ryan TA, Gerber DJ (July 2013). "Working Memory Impairment in Calcineurin Knock-out Mice Is Associated with Alterations in Synaptic Vesicle Cycling and Disruption of High-Frequency Synaptic and Network Activity in Prefrontal Cortex". J. Neurosci. 33 (27): 10938–49. doi:10.1523/JNEUROSCI.5362-12.2013. PMID 23825400. 
• Crabtree GR (1999). "Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT". Cell 96 (5): 611–4. doi:10.1016/S0092-8674(00)80571-1. PMID 10089876. 
• Giri PR, Higuchi S, Kincaid RL (1992). "Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit". Biochem. Biophys. Res. Commun. 181 (1): 252–8. doi:10.1016/S0006-291X(05)81410-X. PMID 1659808. 
• Kincaid RL, Giri PR, Higuchi S, et al. (1990). "Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods". J. Biol. Chem. 265 (19): 11312–9. PMID 2162844. 
• Guerini D, Klee CB (1990). "Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain". Proc. Natl. Acad. Sci. U.S.A. 86 (23): 9183–7. doi:10.1073/pnas.86.23.9183. PMC 298458. PMID 2556704. 
• Kincaid RL, Nightingale MS, Martin BM (1988). "Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin". Proc. Natl. Acad. Sci. U.S.A. 85 (23): 8983–7. doi:10.1073/pnas.85.23.8983. PMC 282646. PMID 2848250. 
• Coghlan VM, Perrino BA, Howard M, et al. (1995). "Association of protein kinase A and protein phosphatase 2B with a common anchoring protein". Science 267 (5194): 108–11. doi:10.1126/science.7528941. PMID 7528941. 
• Griffith JP, Kim JL, Kim EE, et al. (1995). "X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex". Cell 82 (3): 507–22. doi:10.1016/0092-8674(95)90439-5. PMID 7543369. 
• Shibasaki F, McKeon F (1995). "Calcineurin functions in Ca(2+)-activated cell death in mammalian cells". J. Cell Biol. 131 (3): 735–43. doi:10.1083/jcb.131.3.735. PMC 2120616. PMID 7593193. 
• Muramatsu T, Kincaid RL (1993). "Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha)". Biochim. Biophys. Acta 1178 (1): 117–20. doi:10.1016/0167-4889(93)90117-8. PMID 8392375. 
• Cameron AM, Steiner JP, Roskams AJ, et al. (1996). "Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux". Cell 83 (3): 463–72. doi:10.1016/0092-8674(95)90124-8. PMID 8521476. 
• Kissinger CR, Parge HE, Knighton DR, et al. (1996). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. doi:10.1038/378641a0. PMID 8524402. 
• Wang MG, Yi H, Guerini D, et al. (1997). "Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21→q22 and 2p16→p15 respectively". Cytogenet. Cell Genet. 72 (2–3): 236–41. doi:10.1159/000134198. PMID 8978785. 
• Shibasaki F, Kondo E, Akagi T, McKeon F (1997). "Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2". Nature 386 (6626): 728–31. doi:10.1038/386728a0. PMID 9109491. 
• Kashishian A, Howard M, Loh C, et al. (1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. doi:10.1074/jbc.273.42.27412. PMID 9765270. 
• Wang HG, Pathan N, Ethell IM, et al. (1999). "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science 284 (5412): 339–43. doi:10.1126/science.284.5412.339. PMID 10195903. 
• Fuentes JJ, Genescà L, Kingsbury TJ, et al. (2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. doi:10.1093/hmg/9.11.1681. PMID 10861295. 
• Hartley JL, Temple GF, Brasch MA (2001). "DNA Cloning Using In Vitro Site-Specific Recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. 
• Frey N, Richardson JA, Olson EN (2001). "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14632–7. doi:10.1073/pnas.260501097. PMC 18970. PMID 11114196. 
• Siddiq A, Miyazaki T, Takagishi Y, et al. (2001). "Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism". Endocrinology 142 (5): 1752–9. doi:10.1210/en.142.5.1752. PMID 11316738. 

External links

• Calcineurin at the US National Library of Medicine Medical Subject Headings (MeSH)
• Calcineurin at eMedicine Dictionary

English Journal

• Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer's disease.

• Dao AT, Zagaar MA, Salim S, Eriksen JL, Alkadhi KA.Author information University of Houston, College of Pharmacy, Houston, TX, USA.AbstractPreviously, we reported that in a rat model of sporadic Alzheimer's disease (AD) generated by exogenous administration of Aβ1-42 (250 pmol/d for 2 wk) via mini-osmotic pump, the animals exhibited learning and memory impairment, which could be attributed to the deleterious alterations in the levels of cognition-related signalling molecules. We showed that 4 wk of treadmill exercise totally prevented these impairments. Here, we evaluated the effect of exercise on non-cognitive function and basal synaptic transmission in the Cornu Ammonis 1 (CA1) area using the same AD model. Our results indicated that the anxiety behaviour of Aβ-treated rats was prevented by 4 wk of treadmill exercise. Exercised/Aβ-infused rats spent a longer time in the centre area of the open field (OF), elevated plus maze (EPM) paradigms and the light area of the light-dark (LD) box, which were similar to those of control and exercise rats. Furthermore, under basal conditions the aberrant up-regulation of calcineurin (PP2B) and reduction of phosphorylated Ca2+/calmodulin dependent protein kinase II (p-CaMKII) levels induced by AD-like pathology were normalised by the exercise regimen. We conclude that regular exercise may exert beneficial effects on both cognitive and non-cognitive functions in this AD model.
• The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP).Int J Neuropsychopharmacol.2014 Apr;17(4):593-602. doi: 10.1017/S1461145713001351. Epub 2013 Nov 14.
• Previously, we reported that in a rat model of sporadic Alzheimer's disease (AD) generated by exogenous administration of Aβ1-42 (250 pmol/d for 2 wk) via mini-osmotic pump, the animals exhibited learning and memory impairment, which could be attributed to the deleterious alterations in the levels
• PMID 24229510

• Direct association of the unique C-terminal tail of transmembrane AMPA receptor regulatory protein γ-8 with calcineurin.

• Itakura M1, Watanabe I, Sugaya T, Takahashi M.Author information 1Department of Biochemistry, Kitasato University School of Medicine, Kanagawa, Japan.AbstractTransmembrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor regulatory proteins (TARPs) are auxiliary subunits that regulate AMPA receptor trafficking to the plasma membrane and localization to postsynaptic sites. The classical TARP family consists of four members: stargazin/γ-2, γ-3, γ-4 and γ-8. The TARP γ-8 isoform, which is highly expressed in the hippocampus, has a unique, long C-terminal domain with five distinct regions: two glycine-rich regions, a serine/arginine-rich region, a proline/alanine (P/A) rich region, and a PSD-95/Dlg/ZO-1 (PDZ) binding motif. We performed mass spectrometry and immunoprecipitation assays to identify specific binding partners for the γ-8 C-terminal tail and found that γ-8, but not stargazin/γ-2, co-immunoprecipitated with calcineurin/PP2B, a Ca(2+) /calmodulin-dependent Ser/Thr phosphatase. Co-immunoprecipitation and immunoblot analyses of lysates from COS-7 cells co-transfected with calcineurin and either wild type or chimeric γ-8 revealed that a section of the C-terminal tail (residues 356-421) can bind calcineurin. Futhermore, γ-8 lacking the P/A-rich region (residues 383-399) did not bind to calcineurin. In addition, the GST-γ-8 C-terminal tail (residues 353-414) fusion protein containing the P/A-rich region bound to purified calcineurin in a Ca(2+) /calmodulin-dependent manner, whereas GST-γ-8 with a deletion of the P/A-rich region did not. Peptide competition assays demonstrated that γ-8 may interact with the hydrophobic pocket defined by β-sheet 14 and/or adjacent regions of the catalytic A subunit of calcineurin. These results indicate that the γ-8 P/A-rich region is essential for binding calcineurin, suggesting that the γ-8/calcineurin complex may regulate AMPA receptor phosphorylation and trafficking.
• The FEBS journal.FEBS J.2014 Mar;281(5):1366-78. doi: 10.1111/febs.12708. Epub 2014 Jan 27.
• Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor regulatory proteins (TARPs) are auxiliary subunits that regulate AMPA receptor trafficking to the plasma membrane and localization to postsynaptic sites. The classical TARP family consists of four members: stargazin/γ-
• PMID 24418105

• A novel assay method for calcium calmodulin dependent phosphatase from bovine brain extract.

• Devaraju KS1, Kumar BS2, Sureshbabu SV3, Gopi A4, Saraswathi R4, Harish BM4.Author information 1Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore 560 029, India. ksdevaraju@bub.ernet.in2Department of Zoology, Maharani's Science College for Women, Bangalore 560 056, India.3Department of Clinical Research, Padmashree Group of Institutions, Bangalore 560 072, India.4Department of Biotechnology, Bangalore University, Bangalore 560 056, India.AbstractCalcium calmodulin dependent protein ser/thr phosphatase, also referred to as protein phosphatase 2B (PP2B), is rich in neural tissue, and plays an important role in the overall function of the nervous system. Routinely phosphatase assay employs, para-Nitrophenlylphosphate (p-NPP), as a substrate, is also extended to assay PP2B. However, in the present study, the differential spectral characterstic property of tyrosine and phopshotyrosine has been exploited to employ the latter as a candidate substrate for the PP2B assay. The specific activity of PP2B using phosphortyrosine in bovine Bos Taurus indicus brain extract (Bos Taurus indicus), was measured in presence of different metal ions like Ca(2+), Mn(2+) and Mg(2+). Further modulators like dithiothreitol (DTT), calmodulin (CaM) and metal chelators such as EGTA and EDTA were applied to confirm the role of divalent cations and to determine calcium calmodulin dependent phoshphatase activity. PP2B activity was higher with phosphotyrosine in presence of Ca(2+) than with p-NPP. Further experiments, involving calmodulin as a modulator, confirmed phosphotyrosine as a better substrate over p-NPP. Calmodulin further enhanced the effect of phosphotyrosine as a potential substrate confirming calcium calmodulin dependent phosphatase activity. Phosphotyrosine is proposed as a better substrate in assaying calcium dependent phosphatase activity when compared to para-nitrophenylphosphate.
• Indian journal of experimental biology.Indian J Exp Biol.2014 Feb;52(2):168-74.
• Calcium calmodulin dependent protein ser/thr phosphatase, also referred to as protein phosphatase 2B (PP2B), is rich in neural tissue, and plays an important role in the overall function of the nervous system. Routinely phosphatase assay employs, para-Nitrophenlylphosphate (p-NPP), as a substrate, i
• PMID 24597150

Japanese Journal

• ストレス依存的に引き起こされるマウスSNAP-25の脱リン酸化機構の検討

• 飯田 諭宜,山森 早織,板倉 誠 [他]
• 北里医学 = Kitasato medicine 43(1), 31-36, 2013-06
• NAID 40019756636

• Regulation of the catalytic domain of protein phosphatase 1 by the terminal region of protein phosphatase 2B

• WANG Bai J.,TANG Wei,ZHANG Peng,WEI Qun
• The journal of biochemistry 151(3), 283-290, 2012-03-01
• NAID 10031166067

• Regulation of the catalytic domain of protein phosphatase 1 by the terminal region of protein phosphatase 2B

• Wang Bai J.,Tang Wei,Zhang Peng [他]
• Journal of Biochemistry 151(3), 283-290, 2012-03
• NAID 40019186005

Related Links

• PP2B Inhibitor sc-3055 | Santa Cruz Biotech

PP2B Inhibitor sc-3055. ... synthetic inhibitor for PP2B, 0.5 mg/0.1 ml; sequence: ITSFEEAKGLDRINERMPPRRDAMP (>97% pure by HPLC); derived from PP2B auto-inhibitory domain from rat brain calcineuron A α, residues 457-482; also ...

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リンク元	「プロテインホスファターゼ2B」「protein phosphatase 2B」
関連記事	「PP」

「プロテインホスファターゼ2B」

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英

protein phosphatase 2B、PP2B

関

カルシニューリン

「protein phosphatase 2B」

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プロテインホスファターゼ2B

関

calcineurin、PP2B

「PP」

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• ポリプロピレン polypropylene
• 血漿交換 プラスマフェレーシス plasmapheresis
• 膵ポリペプチド pancreatic polypeptide