Genomes and Genes
Gene Symbol: PPP3CA
Description: protein phosphatase 3 catalytic subunit alpha
Alias: CALN, CALNA, CALNA1, CCN1, CNA1, IECEE, IECEE1, PPP2B, serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform, CAM-PRP catalytic subunit, calcineurin A alpha, calmodulin-dependent calcineurin A subunit alpha isoform, protein phosphatase 2B, catalytic subunit, alpha isoform, protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform, protein phosphatase 3 catalytic subunit alpha isozyme
Publications119 found, 100 shown here
- Kissinger C, Parge H, Knighton D, Lewis C, Pelletier L, Tempczyk A, et al. Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature. 1995;378:641-4 pubmed..The site of binding of FKBP12-FK506 appears to be shared by other non-competitive inhibitors of calcineurin, including a natural anchoring protein. ..
- Sun L, Youn H, Loh C, Stolow M, He W, Liu J. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity. 1998;8:703-11 pubmed..These results suggest a negative regulatory role for Cabin 1 in calcineurin signaling and provide a possible mechanism of feedback inhibition of TCR signaling through cross-talk between protein kinases and calcineurin. ..
- Kashishian A, Howard M, Loh C, Gallatin W, Hoekstra M, Lai Y. AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region. J Biol Chem. 1998;273:27412-9 pubmed..These results demonstrated that AKAP79 can bind to and inhibit calcineurin activity in vivo, suggesting a physiological role for AKAP79-calcineurin interaction in NFAT-mediated signaling. ..
- Fuentes J, Genescà L, Kingsbury T, Cunningham K, Pérez Riba M, Estivill X, et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet. 2000;9:1681-90 pubmed..Together, these results suggest that members of this newly described family of human proteins are endogenous regulators of calcineurin-mediated signaling pathways and as such, they may be involved in many physiological processes. ..
- Huai Q, Kim H, Liu Y, Zhao Y, Mondragon A, Liu J, et al. Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes. Proc Natl Acad Sci U S A. 2002;99:12037-42 pubmed..The comparison of CyPA-CsA-CN with FKBP-FK506-CN significantly contributes to understanding the molecular basis of regulation of CN activity by the immunophilin-immunosuppressant. ..
- Linden M, Sheldon R, Meers G, Ortinau L, Morris E, Booth F, et al. Aerobic exercise training in the treatment of non-alcoholic fatty liver disease related fibrosis. J Physiol. 2016;594:5271-84 pubmed publisher..factor-? protein and ?-smooth muscle actin mRNA), whereas EX increased the hepatic stellate cell senescence marker CCN1 (P < 0.01 vs. O-SED)...
- Chen C, Jiang X, Li Y, Yu H, Li S, Zhang Z, et al. Low-dose oral copper treatment changes the hippocampal phosphoproteomic profile and perturbs mitochondrial function in a mouse model of Alzheimer's disease. Free Radic Biol Med. 2019;135:144-156 pubmed publisher..synthase kinase-3 beta (GSK3β) and serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform (Ppp3ca), which involved mitochondrial biogenesis signaling...
- Degani G, Ragni E, Botías P, Ravasio D, Calderon J, Pianezzola E, et al. Genomic and functional analyses unveil the response to hyphal wall stress in Candida albicans cells lacking ?(1,3)-glucan remodeling. BMC Genomics. 2016;17:482 pubmed publisher..DNA replication genes associated with entry into S-phase occurred whereas cell-cycle regulating genes (PCL1, PCL2, CCN1, GIN4, DUN1, CDC28) were persistently up-regulated...
- Twigg S. Regulation and bioactivity of the CCN family of genes and proteins in obesity and diabetes. J Cell Commun Signal. 2018;12:359-368 pubmed publisher..In contrast, CCN1, CCN2 and possibly CCN3, may have a reparative role in wound healing in diabetes, and CCN2 in islet cell ..
- Murphy Marshman H, Quensel K, Shi wen X, Barnfield R, Kelly J, Peidl A, et al. Antioxidants and NOX1/NOX4 inhibition blocks TGF?1-induced CCN2 and ?-SMA expression in dermal and gingival fibroblasts. PLoS ONE. 2017;12:e0186740 pubmed publisher..In HDF and HGF, TGFbeta1 induces CCN2, CCN1, endothelin-1 and alpha-smooth muscle actin (SMA) in a fashion sensitive to NAC...
- Sidler M, Aitken K, Jiang J, Sotiropoulos C, Aggarwal P, Anees A, et al. DNA Methylation Reduces the Yes-Associated Protein 1/WW Domain Containing Transcription Regulator 1 Pathway and Prevents Pathologic Remodeling during Bladder Obstruction by Limiting Expression of BDNF. Am J Pathol. 2018;188:2177-2194 pubmed publisher..Expression of BDNF is limited by DNA methylation and associated with pathophysiologic changes during partial bladder outlet obstruction and SMC phenotypic change in vitro. ..
- Zoppi N, Chiarelli N, Binetti S, Ritelli M, Colombi M. Dermal fibroblast-to-myofibroblast transition sustained by ?vß3 integrin-ILK-Snail1/Slug signaling is a common feature for hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Biochim Biophys Acta Mol Basis Dis. 2018;1864:1010-1023 pubmed publisher..augmented levels of the ECM-degrading metalloproteinase-9, and altered expression of the inflammation mediators CCN1/CYR61 and CCN2/CTGF...
- Yu O, Brown J. G Protein-Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation. Mol Pharmacol. 2015;88:171-80 pubmed publisher..the inflammatory mediator cyclooxygenase 2, and the matricellular protein cysteine-rich angiogenic inducer 61 (CCN1)...
- Ritz M, Graumann U, Gutierrez B, Hausmann O. Traumatic spinal cord injury alters angiogenic factors and TGF-beta1 that may affect vascular recovery. Curr Neurovasc Res. 2010;7:301-10 pubmed..1 (TGF-?1) were elevated at every time point following SCI, whereas those encoding for the cysteine-rich protein CCN1/CYR61 were upregulated after 2 h, 6 h, and 1 week only...
- Dias M, Canovas A, Mantilla Rojas C, Riley D, Luna Nevarez P, Coleman S, et al. SNP detection using RNA-sequences of candidate genes associated with puberty in cattle. Genet Mol Res. 2017;16: pubmed publisher..Overall, 172 SNPs within 13 genes (CPNE5, FAM19A4, FOXN4, KLF1, LOC777593, MGC157266, NEBL, NRXN3, PEPT-1, PPP3CA, SCG5, TSG101, and TSHR) were concordant in the five breeds...
- Young K, Tweedie E, Conley B, Ames J, FitzSimons M, Brooks P, et al. BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. PLoS ONE. 2015;10:e0122892 pubmed publisher..Suppression of endoglin and YAP1 alters BMP9-dependent expression of YAP1 target genes CCN1 (cysteine-rich 61, CYR61) and CCN2 (connective tissue growth factor, CTGF) as well as the chemokine CCL2 (monocyte ..
- Liu X, Hong Q, Wang Z, Yu Y, Zou X, Xu L. Transforming growth factor-Î²-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells. Exp Biol Med (Maywood). 2016;241:265-72 pubmed publisher..markedly decreased the expression and deposition of type I collagen, fibronectin (Fn), cysteine-rich protein 61 (CCN1), Î±-smooth muscle actin, and fibroblast-specific protein1 in TGF-Î²-treated TECs...
- Fu C, Donadio N, Cardenas M, Heitman J. Dissecting the Roles of the Calcineurin Pathway in Unisexual Reproduction, Stress Responses, and Virulence in Cryptococcus deneoformans. Genetics. 2018;208:639-653 pubmed publisher..Finally, we showed that deletion of PBP1 or TIF3 in the cna1∆ mutant background conferred a modest level of growth tolerance at 37°, but that the cna1∆ pbp1Roberts D, Kaur S, Isenberg J. Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer. Antioxid Redox Signal. 2017;27:874-911 pubmed publisher..The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan ..Kimura T, Duggirala A, Smith M, White S, Sala Newby G, Newby A, et al. The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP. J Mol Cell Cardiol. 2016;90:1-10 pubmed publisher..Forskolin significantly inhibited the mRNA expression of the pro-mitogenic genes, CCN1, CTGF, c-MYC and TGFB2 and this was reversed by expression of constitutively-active YAP or TAZ phospho-mutants...Zhou H, Yao Y, Liang Y, Wang Z, Zhou X, Guo W, et al. [Screening of key molecules of HAb18G/CD147 signal transduction pathway in human hepatoma cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017;33:1196-1200 pubmed..protein-2 (BMP-2), BMP-5, endothelin-1 (ET-1), Wnt1-induced signaling proteins-2/CCN5 (WISP-2), cysteine-rich 61/CCN1 (Cyr61), prostate stem cell antigen (PSCA), and the up-regulated genes included interleukin-10 receptor Î± (IL-..Yamashita T, Asano Y, Saigusa R, Taniguchi T, Hirabayashi M, Miyagawa T, et al. Cyclophosphamide Pulse Therapy Normalizes Vascular Abnormalities in a Mouse Model of Systemic Sclerosis Vasculopathy. J Invest Dermatol. 2019;139:1150-1160 pubmed publisher..the decreased expression of vascular endothelial cadherin, platelet-derived growth factor B, S1P1, and CCN1 (molecules associated with angiogenesis and/or vasculogenesis) was reversed along with the reversal of endothelial ..Redgrove K, Bernstein I, Pye V, Mihalas B, Sutherland J, Nixon B, et al. Dynamin 2 is essential for mammalian spermatogenesis. Sci Rep. 2016;6:35084 pubmed publisher..We also demonstrate that DNM2 activity may be temporally regulated by phosphorylation of DNM2 via the kinase CDK1 in spermatogonia, and dephosphorylation by phosphatase PPP3CA during meiotic and post-meiotic spermatogenesis.Kochi Y, Matsumoto Y, Sekimizu K, Kaito C. Two-spotted cricket as an animal infection model of human pathogenic fungi. Drug Discov Ther. 2017;11:259-266 pubmed publisher..C. neoformans gene-knockout strains of cna1, gpa1, and pka1, which are required for virulence in mammals, had greater LD50 values than the parent strain in ..Hara C, Kubota S, Nishida T, Hiasa M, Hattori T, Aoyama E, et al. Involvement of multiple CCN family members in platelets that support regeneration of joint tissues. Mod Rheumatol. 2016;26:940-949 pubmed publisher..Furthermore, we found for the first time CCN5 and CCN1 that inhibits ADAMTS4 in both platelets and megakaryocytes...Cohen T, Jones Nelson O, Hotz M, Cheng L, Miller L, Suzich J, et al. S. aureus blocks efferocytosis of neutrophils by macrophages through the activity of its virulence factor alpha toxin. Sci Rep. 2016;6:35466 pubmed publisher..AT significantly reduced lung expression of CCN1 and altered AM surface localization of DD1Î±, two proteins known to influence efferocytosis...Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis. J Am Coll Cardiol. 2016;67:2018-28 pubmed publisher..7%; p < 0.01), and was associated with impaired cardiac function. Conversely, cardiac-specific expression of CCN1 (CYR61), a potent inducer of premature senescence, by adeno-associated virus serotype 9 gene transfer, resulted in ?..Chen J, Balakrishnan Renuka A, Hagemann N, Theiss C, Chankiewitz V, Chen J, et al. A novel interaction between ATOH8 and PPP3CB. Histochem Cell Biol. 2016;145:5-16 pubmed publisher..of PPP3CB is conserved among all isoforms of calcineurin A, ATOH8 selectively interacts with PPP3CB instead of PPP3CA, probably due to the unique proline-rich region present in the N-terminus of PPP3CB, which controls the ..Yang W, Han W, Qin A, Wang Z, Xu J, Qian Y. The emerging role of Hippo signaling pathway in regulating osteoclast formation. J Cell Physiol. 2017;: pubmed publisher..of downstream target genes such as connective tissue growth factor (CTGF/CCN2) and cysteine-rich protein 61 (CYR61/CCN1)...Seo J, Lee S, Shin J, Hwang Y, Cho H, Yoo S, et al. Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy. Exp Mol Med. 2017;49:e333 pubmed publisher..Using cell lines and animal models, we also showed that reduced PPP3CA/PP2B phosphatase activity is directly associated with increases in phosphorylated (p)-tau proteins...LeMaire S, Raghuram V, Grady C, Pickering C, Chou C, Umejiego E, et al. Serine/threonine phosphatases and aquaporin-2 regulation in renal collecting duct. Am J Physiol Renal Physiol. 2017;312:F84-F95 pubmed publisher..to the top-ranked phosphatases (common names in parentheses) were: Ppp1cb (PP1-?), Ppm1g (PP2C), Ppp1ca (PP1-?), Ppp3ca (PP2-B or calcineurin), Ppp2ca (PP2A-?), Ppp1cc (PP1-?), Ppp2cb (PP2A-?), Ppp6c (PP6C), and Ppp5c (PP5)...Zhu H, Gao W, Jiang H, Wu J, Shi Y, Zhang X. Calcineurin mediates acetylcholinesterase expression during calcium ionophore A23187-induced HeLa cell apoptosis. Biochim Biophys Acta. 2007;1773:593-602 pubmed..These results indicate that calcineurin mediates acetylcholinesterase expression during apoptosis. ..Frey N, Richardson J, Olson E. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A. 2000;97:14632-7 pubmed..Calsarcins represent a novel family of sarcomeric proteins that link calcineurin with the contractile apparatus, thereby potentially coupling muscle activity to calcineurin activation. ..Mukerjee N, McGinnis K, Gnegy M, Wang K. Caspase-mediated calcineurin activation contributes to IL-2 release during T cell activation. Biochem Biophys Res Commun. 2001;285:1192-9 pubmed..Taken together, our results suggest that caspase-mediated cleavage of Cn A contributes to IL-2 production during T cell activation. ..San Antonio B, Iñiguez M, Fresno M. Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity. J Biol Chem. 2002;277:27073-80 pubmed..These data reveal a new role of PKCzeta in T cells through the control of NFAT function by modulating the activity of its transactivation domain. ..Wada A, Kunii Y, Ikemoto K, Yang Q, Hino M, Matsumoto J, et al. Increased ratio of calcineurin immunoreactive neurons in the caudate nucleus of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:8-14 pubmed publisher..This is the first report of caudate CaN abnormalities in schizophrenia. ..Muili K, Jin S, Orabi A, Eisses J, Javed T, Le T, et al. Pancreatic acinar cell nuclear factor ?B activation because of bile acid exposure is dependent on calcineurin. J Biol Chem. 2013;288:21065-73 pubmed publisher..In summary, bile-induced NF-?B activation and acinar cell injury are mediated by calcineurin, and a mechanism for this important early inflammatory response appears to be upstream at the level of PKC translocation. ..Krupska I, Bruford E, Chaqour B. Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities. Hum Genomics. 2015;9:24 pubmed publisher..The CCN genes can be subdivided into members developmentally indispensable for embryonic viability (e.g., CCN1, 2 and 5), each assuming unique tissue-specific functions, and members not essential for embryonic development (e.g...Jeinsen N, Mägel L, Jonigk D, Klingenberg M, Haverich A, Wilhelmi M, et al. Biocompatibility of Intensified Decellularized Equine Carotid Arteries in a Rat Subcutaneous Implantation Model and in a Human In Vitro Model. Tissue Eng Part A. 2018;24:310-321 pubmed publisher..b>CCN1 has been shown to improve biocompatibility of dEACcon in a sheep model...Chen B, Huang C, Chang W, Chen Y, Kikkawa U, Nakahama K, et al. PP2B-mediated dephosphorylation of c-Jun C terminus regulates phorbol ester-induced c-Jun/Sp1 interaction in A431 cells. Mol Biol Cell. 2007;18:1118-27 pubmed..These findings indicate the dephosphorylation of c-Jun C terminus is required for the c-Jun/Sp1 interaction and reveal that PP2B plays an important role in regulating c-Jun/Sp1 interaction in PMA-induced gene expression. ..Liu Y, Guo Y, Zhang L, Pei Y, Yu N, Yu P, et al. Biological pathway-based genome-wide association analysis identified the vasoactive intestinal peptide (VIP) pathway important for obesity. Obesity (Silver Spring). 2010;18:2339-46 pubmed publisher..The study also highlights the importance of pathway-based GWA analysis in identification of additional genes/variants for complex human diseases. ..Zhao J, Gao Z, Ji Q, Wang H, Zhang H, Yang Y, et al. Regulation of cofilin activity by CaMKII and calcineurin. Am J Med Sci. 2012;344:462-72 pubmed publisher..Based on these findings, the authors suggest that CaMKII and Cn provide a switch-like mechanism that controls Ca-dependent LIMK1, SSH1L and cofilin activation, and subsequently actin cytoskeletal reorganization. ..Lee H, Hwang S, Kim H, Shin C, Choi K, Joung J, et al. Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p. Biochim Biophys Acta. 2016;1859:599-611 pubmed publisher..NF2 also controlled the expression of YAP targets, including cysteine-rich angiogenic inducer 61 (CYR61/CCN1), by regulating the nuclear localization of YAP...Zhang L, Zhang J, Liu S, Nian H, Chen L. Characterization of calcineurin from Cryptococcus humicola and the application of calcineurin in aluminum tolerance. BMC Biotechnol. 2017;17:35 pubmed publisher..The binding affinities of CNA1 and CNA2, in which I439 or I443 were replaced by Ala, were decreased relative to wild-type CNA...Zhang Y, Zheng Y, Xu R, Chen H, Zhu Y, Zhang Y, et al. WITHDRAWN: USP14 stabilizes calcineurin and regulates NFAT/AP-1 dependent IL-4 transcription as a novel calcineurin-binding protein. FEBS Lett. 2009;: pubmed..The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. ..Hwang S, Lee H, Kim G, Won K, Park Y, Jo I. CCN1 acutely increases nitric oxide production via integrin Î±vÎ²3-Akt-S6K-phosphorylation of endothelial nitric oxide synthase at the serine 1177 signaling axis. Free Radic Biol Med. 2015;89:229-40 pubmed publisherAlthough CCN1 (also known as cysteine-rich, angiogenic inducer 61, CYR61) has been reported to promote angiogenesis and neovascularization in endothelial cells (ECs), its effects on endothelial nitric oxide (NO) production have never been ..Yao J, Zhao Q, Liu D, Chow C, Mei Y. Neuritin Up-regulates Kv4.2 ?-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway. J Biol Chem. 2016;291:17369-81 pubmed publisher..Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions. ..Chen C, Su C, Hsu C, Huang C, Wang S, Liu S, et al. CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angiogenesis by Inhibiting miR-126 Expression in Rheumatoid Arthritis. J Bone Miner Res. 2017;32:34-45 pubmed publisher..Cysteine-rich 61 (Cyr61 or CCN1) is an important proinflammatory cytokine in RA...Chen J, Liu Y, Sun Q, Wang B, Li N, Chen X. CYR61 suppresses growth of human malignant melanoma. Oncol Rep. 2016;36:2697-2704 pubmed publisherCysteine-rich protein 61 (CCN1/CYR61) is an important marker of proliferation and metastasis in malignant melanoma, making it a potential target for melanoma treatment...Nygren P, Scott J. Regulation of the phosphatase PP2B by protein-protein interactions. Biochem Soc Trans. 2016;44:1313-1319 pubmed..Finally, we discuss potential for targeting PP2B anchoring motifs for therapeutic benefit. ..Kim K, Won J, Cheng N, Lau L. The matricellular protein CCN1 in tissue injury repair. J Cell Commun Signal. 2018;12:273-279 pubmed publisherThe expression of Ccn1 (Cyr61) is essential for cardiovascular development during embryogenesis, whereas in adulthood it is associated with inflammation, wound healing, injury repair, and related pathologies including fibrosis and cancer...Niwa Y, Suzuki T, Dohmae N, Simizu S. O-Fucosylation of CCN1 is required for its secretion. FEBS Lett. 2015;589:3287-93 pubmed publisherThe matricellular protein CCN1, also known as Cyr61, is a secreted ligand and has numerous functions. Human CCN1 contains one predicted O-fucosylation site in the thrombospondin type-1 repeat (TSR1) domain at Thr(242)...Sheftic S, Page R, Peti W. Investigating the human Calcineurin Interaction Network using the ??LxVP SLiM. Sci Rep. 2016;6:38920 pubmed publisher..This combined structural-bioinformatics approach provides a powerful method for dissecting the CN interaction network and for elucidating the role of CN in human health and disease. ..Li Z, Wu W, Zhao C, Zhang X, Yang Z, Pan J, et al. CCN1/Cyr61 enhances the function of hepatic stellate cells in promoting the progression of hepatocellular carcinoma. Int J Mol Med. 2018;41:1518-1528 pubmed publisher..Cysteine?rich 61 (CCN1/Cyr61) is an ECM protein...Medina D, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R, et al. Lysosomal calcium signalling regulates autophagy through calcineurin and â€‹TFEB. Nat Cell Biol. 2015;17:288-99 pubmed..These data link lysosomal calcium signalling to both calcineurin regulation and autophagy induction and identify the lysosome as a hub for the signalling pathways that regulate cellular homeostasis. ..Lau L. Cell surface receptors for CCN proteins. J Cell Commun Signal. 2016;10:121-7 pubmed publisherThe CCN family (CYR61; CTGF; NOV; CCN1-6; WISP1-3) of matricellular proteins in mammals is comprised of six homologous members that play important roles in development, inflammation, tissue repair, and a broad range of pathological ..Lv S, Qiu X, Li J, Li W, Zhang C, Zhang Z, et al. Suppression of CRTC2-mediated hepatic gluconeogenesis by TRAF6 contributes to hypoglycemia in septic shock. Cell Discov. 2016;2:16046 pubmed..These results suggest that pro-inflammatory signals intersect with the CRTC2 pathway in liver, thus contributing to hypoglycemia caused by infection. ..Shibasaki F, McKeon F. Calcineurin functions in Ca(2+)-activated cell death in mammalian cells. J Cell Biol. 1995;131:735-43 pubmed..These data suggest that calcineurin plays an important role in mediating the upstream events in calcium-activated cell death. ..Siddiq A, Miyazaki T, Takagishi Y, Kanou Y, Hayasaka S, Inouye M, et al. Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism. Endocrinology. 2001;142:1752-9 pubmedYamashiro T, Kuge H, Zhang J, Honke K. Calcineurin mediates the angiotensin II-induced aldosterone synthesis in the adrenal glands by up-regulation of transcription of the CYP11B2 gene. J Biochem. 2010;148:115-23 pubmed publisher..Taken together, we conclude that CN mediates the Ang II-induced aldosterone synthesis through up-regulation of the CYP11B2 transcription. ..Di Y, Zhang Y, Hui L, Yang H, Yang Y, Wang A, et al. Cysteine?rich 61 RNA interference inhibits pathological angiogenesis via the phosphatidylinositol 3?kinase/Akt?vascular endothelial growth factor signaling pathway in endothelial cells. Mol Med Rep. 2016;14:4321-4327 pubmed publisherHypoxia is a key factor in the pathogenesis of angiogenesis, and cysteine?rich 61 (CCN1), an angiogenic factor, is involved in the development of pathological angiogenesis...Li H, Kedar V, Zhang C, McDonough H, Arya R, Wang D, et al. Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest. 2004;114:1058-71 pubmedZhu H, Suk H, Yu R, Brancho D, Olabisi O, Yang T, et al. Evolutionarily conserved role of calcineurin in phosphodegron-dependent degradation of phosphodiesterase 4D. Mol Cell Biol. 2010;30:4379-90 pubmed publisher..This novel signaling system also provides unique functional insights into the complications elicited by CsA in transplant patients. ..Shibasaki F, Kondo E, Akagi T, McKeon F. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Nature. 1997;386:728-31 pubmed..We propose that the ability of Bcl-2 to block NF-AT signalling is due to the sequestering of active calcineurin to the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and that calcineurin may act in Bcl-2-regulated functions. ..Brogan I, Pravica V, Hutchinson I. Genetic conservation of the immunophilin-binding domains of human calcineurin A1 and A2. Transpl Immunol. 2000;8:139-41 pubmed..In humans two separate genes, CNA1 and CNA2, encode the calcineurin A (CNA) subunit...Cao X, Kambe F, Miyazaki T, Sarkar D, Ohmori S, Seo H. Novel human ZAKI-4 isoforms: hormonal and tissue-specific regulation and function as calcineurin inhibitors. Biochem J. 2002;367:459-66 pubmed..These results suggest that the expression of ZAKI-4 isoforms is subjected to distinct hormonal as well as tissue-specific regulation, constituting a complex signalling network through inhibition of calcineurin. ..Zekri A, Hassan Z, Bahnassy A, Sherif G, Eldahshan D, Abouelhoda M, et al. Molecular prognostic profile of Egyptian HCC cases infected with hepatitis C virus. Asian Pac J Cancer Prev. 2012;13:5433-8 pubmed..The validation for the microarray was done by real time PCR assay in which PPP3CA, ATG-5, BACE genes showed down-regulation and ABCG2, RXRA, ELOVL2, CXR3 genes showed up-regulation...Grigoriu S, Bond R, Cossio P, Chen J, Ly N, Hummer G, et al. The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin. PLoS Biol. 2013;11:e1001492 pubmed publisher..Collectively, this work presents the first integrated structural model for substrate selection and dephosphorylation by CN and lays the groundwork for structure-based development of new CN inhibitors. ..Li S, Fell S, Surova O, Smedler E, Wallis K, Chen Z, et al. The 1p36 Tumor Suppressor KIF 1BÎ² Is Required for Calcineurin Activation, Controlling Mitochondrial Fission and Apoptosis. Dev Cell. 2016;36:164-78 pubmed publisher..Importantly, KIF1BÎ² and DRP1 are silenced in 1p36 hemizygous-deleted neuroblastomas, indicating that deregulation of calcineurin and mitochondrial dynamics contributes to high-risk and poor-prognosis neuroblastoma. ..Kincaid R, Giri P, Higuchi S, Tamura J, Dixon S, Marietta C, et al. Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods. J Biol Chem. 1990;265:11312-9 pubmed..The conservation of many regions found in lambda phage phosphatase (Cohen, P.T.W., and Cohen, P. (1989) Biochem. J. 260, 931-934) indicates a common origin for the catalytic domain of this enzyme. ..Ruiz Gomez A, Mellstrom B, Tornero D, Morato E, Savignac M, Holguin H, et al. G protein-coupled receptor kinase 2-mediated phosphorylation of downstream regulatory element antagonist modulator regulates membrane trafficking of Kv4.2 potassium channel. J Biol Chem. 2007;282:1205-15 pubmed..2 channel trafficking and calcineurin de-phosphorylated GRK2-phosphorylated DREAM in vitro. Our results indicate that these two Ca2+-dependent posttranslational events regulate the activity of DREAM on Kv4.2 channel function. ..Finsen A, Lunde I, Sjaastad I, Østli E, Lyngra M, Jarstadmarken H, et al. Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway. PLoS ONE. 2011;6:e28302 pubmed publisher..Thus, our data suggest that manipulation of syndecan-4 may provide an option for therapeutic modulation of calcineurin-NFAT signaling. ..Kincaid R, Nightingale M, Martin B. Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin. Proc Natl Acad Sci U S A. 1988;85:8983-7 pubmed..Thus, the structure of calcineurin is chimeric, consisting of conserved catalytic elements and a regulatory CaM-binding domain. ..Volkel H, Scholz M, Link J, Selzle M, Werner P, Tunnemann R, et al. Superoxide dismutase mutations of familial amyotrophic lateral sclerosis and the oxidative inactivation of calcineurin. FEBS Lett. 2001;503:201-5 pubmedAmato R, Pinelli M, Monticelli A, Miele G, Cocozza S. Schizophrenia and vitamin D related genes could have been subject to latitude-driven adaptation. BMC Evol Biol. 2010;10:351 pubmed publisher..Finally, we discuss a model in which schizophrenia is, at least partly, a maladaptive by-product of latitude dependent adaptive changes in vitamin D metabolism. ..Jin L, Roehrl M, Xiao L, He X, Li H, Ge L, et al. Crystallization and preliminary crystallographic study of a trypsin-resistant catalytic domain of human calcineurin. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012;68:574-9 pubmed publisher..5% solvent content. An X-ray diffraction data set was collected to 2.87 Å resolution and a clear molecular-replacement solution was obtained. The active site of Cncat is open to the solvent channels in the crystal packing. ..Dunlap T, Cook E, Rumi Masante J, Arvin H, Lester T, Creamer T. The distal helix in the regulatory domain of calcineurin is important for domain stability and enzyme function. Biochemistry. 2013;52:8643-51 pubmed publisher..Our data demonstrate the presence of this distal helix and suggest it folds onto the remainder of the RD:CaM complex, creating a hairpinlike chain reversal that removes the AID from the active site. ..Esau C, Boes M, Youn H, Tatterson L, Liu J, Chen J. Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. J Exp Med. 2001;194:1449-59 pubmedWeiwad M, Edlich F, Erdmann F, Jarczowski F, Kilka S, Dorn M, et al. A reassessment of the inhibitory capacity of human FKBP38 on calcineurin. FEBS Lett. 2005;579:1591-6 pubmed..Our data suggest that hFKBP38 cannot substitute for the FKBP/FK506 complex in signaling pathways controlled by the protein phosphatase activity of calcineurin. ..Grybko M, Bartnik J, Wurth G, Pores Fernando A, Zweifach A. Calcineurin activation is only one calcium-dependent step in cytotoxic T lymphocyte granule exocytosis. J Biol Chem. 2007;282:18009-17 pubmed..Taken together, our results support the idea that activation of calcineurin is required for lytic granule exocytosis but suggest that it is not the sole Ca2+-dependent step. ..Polovlkova O, Makeeva O, Lezhnev A, Goncharova I, Kulish E, Shipulin V, et al. [Expression profile of calcineurin pathway genes in myocardium tissues in relation to ischemic heart remodeling in humans]. Mol Biol (Mosk). 2013;47:433-40 pubmed..Results of quantitative expression profiling study of main calcineurin pathway genes PPP3CA, PPP3R1, PPP3CB, GATA4 and NFATC4 in myocardium of right atrium auricle of patients with a coronary heart disease, ..Mishra A, Oulès B, Pisco A, Ly T, Liakath Ali K, Walko G, et al. A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis. elife. 2017;6: pubmed publisher..Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA - promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors...Yang R, Chen Y, Chen D. Biological functions and role of CCN1/Cyr61 in embryogenesis and tumorigenesis in the female reproductive system (Review). Mol Med Rep. 2017;: pubmed publisherCysteine?rich angiogenic inducer 61 (CCN1/Cyr61) is a prompt response transcription product activated by growth factors...Yang D, Ma S, Tan Y, Li D, Tang B, Zhang X, et al. Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure. Int J Mol Med. 2010;26:159-64 pubmedMesquita R, Paul M, Valmaseda A, Francois A, Jabr R, Anjum S, et al. Protein kinase C?-calcineurin cosignaling downstream of toll-like receptor 4 downregulates fibrosis and induces wound healing gene expression in cardiac myofibroblasts. Mol Cell Biol. 2014;34:574-94 pubmed publisher..Therefore, PKC? may negatively regulate adverse myocardial remodeling by cooperating with CN to downregulate fibrosis and induce transcription of cardioprotective wound healing genes, including COX-2. ..Hao F, Zhang F, Wu D, An D, Shi J, Li G, et al. Lysophosphatidic acid-induced vascular neointimal formation in mouse carotid arteries is mediated by the matricellular protein CCN1/Cyr61. Am J Physiol Cell Physiol. 2016;311:C975-C984 pubmed publisher..Our previous study revealed that matricellular protein CCN1, a prominent extracellular matrix (ECM) protein, mediates LPA-induced SMC migration in vitro...King M, Huang C, Chock P, Nairn A, Hemmings H, Chan K, et al. Mammalian brain phosphoproteins as substrates for calcineurin. J Biol Chem. 1984;259:8080-3 pubmed..053 s-1; synapsin I (site II), 0.040 s-1. Comparisons of the catalytic efficiency (kcat/Km) for each substrate indicated that DARPP-32, G-substrate, and Protein K.-F. are all potential substrates for calcineurin in vivo. ..Wang J, Liu S, Haditsch U, Tu W, Cochrane K, Ahmadian G, et al. Interaction of calcineurin and type-A GABA receptor gamma 2 subunits produces long-term depression at CA1 inhibitory synapses. J Neurosci. 2003;23:826-36 pubmed..Thus, an activity-dependent physical and functional interaction between CaN and GABA(A) receptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses. ..Reid S, Zanivan S. Tumor stiffness extends its grip on the metastatic microenvironment. Mol Cell Oncol. 2017;4:e1372866 pubmed publisher..Stiffness-induced expression of CCN1 mediates autocrine signaling in the endothelium to upregulate N-Cadherin levels...Cameron A, Steiner J, Roskams A, Ali S, Ronnett G, Snyder S. Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux. Cell. 1995;83:463-72 pubmed..Calcineurin anchored to the IP3R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca(2+)-sensitive regulation of IP3-mediated Ca2+ flux. ..