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Gene Review

CAST  -  calpastatin

Homo sapiens

Synonyms: Calpain inhibitor, Calpastatin, Sperm BS-17 component
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Disease relevance of CAST

  • Calpastatin is the natural inhibitor of calpains, which are members of the cysteine proteinases recently implicated in joint destruction in rheumatic diseases [1].
  • In Sf9 cells, co-expression of the inhibitor calpastatin was necessary to prevent autolysis of L-muCANP, whereas co-expression of the regulatory subunit enhanced it [2].
  • Further support for the importance of the calpastatin-calpain system was obtained by analyzing neutrophils from patients with cystic fibrosis that exhibited delayed apoptosis, associated with markedly increased calpastatin and decreased calpain-1 protein levels compared with neutrophils from control individuals [3].
  • Overexpression of calpastatin reduced muscle atrophy by 30 % during the 10 day unloading period [4].
  • The longest positive phage clone (1.9 kb) was sequenced and found to be a testis-specific isoform of calpastatin (tCAST) [5].

Psychiatry related information on CAST


High impact information on CAST


Chemical compound and disease context of CAST


Biological context of CAST


Anatomical context of CAST


Associations of CAST with chemical compounds

  • Addition of ALLN/calpain inhibitor I to the culture medium after UV resulted in similar survival (14 - 18%) between RSa and UVr-1 cells [17].
  • Calpastatin is an endogenous inhibitor protein acting specifically on calpain (EC; Ca2(+)-dependent cysteine proteinase) [18].
  • Although MDL 28,170, a calpain inhibitor, prevented the ionomycin-induced processing of precursor IL-1 alpha to the mature protein in P388D1 cells, it did not inhibit the ionomycin-induced secretion of the mature IL-1 alpha and -beta proteins expressed in these cells [23].
  • The calpain inhibitors calpeptin and calpain inhibitor IV significantly inhibited integrin-dependent cell spreading [24].
  • To address the reasons for this discrepancy, Chinese hamster ovary cell lines were established that overexpress the calpain inhibitor protein, calpastatin, under control of the ecdysone congener, ponasterone A [19].

Physical interactions of CAST


Enzymatic interactions of CAST


Regulatory relationships of CAST


Other interactions of CAST

  • These results provide new information about the effects of inflammatory cytokines on calpain and calpastatin system in OA and RA pathology [29].
  • The muM and mM Ca(2+)-sensitive (mu- and mCANP) forms of CANP were separated by DEAE and phenyl Sepharose column chromatography, the latter step enabling removal of the endogenous inhibitor calpastatin [34].
  • Calpain translational expression was up-regulated by 462.5% in MS plaques compared with controls, although levels of the specific endogenous inhibitor, calpastatin, were not altered significantly [35].
  • Similarly, in transient cotransfection assays, expression of the specific inhibitor, calpastatin, partially blocks TNF-alpha-inducible NF-kappaB-dependent promoter activity and IkappaBalpha proteolysis [36].
  • By Western blot analysis, the large subunit of mu-calpain (80 kDa) was found to be eluted with calpastatin (110 kDa) [37].

Analytical, diagnostic and therapeutic context of CAST


  1. Detection and expression of a cDNA clone that encodes a polypeptide containing two inhibitory domains of human calpastatin and its recognition by rheumatoid arthritis sera. Després, N., Talbot, G., Plouffe, B., Boire, G., Ménard, H.A. J. Clin. Invest. (1995) [Pubmed]
  2. Functional properties of recombinant calpain I and of mutants lacking domains III and IV of the catalytic subunit. Vilei, E.M., Calderara, S., Anagli, J., Berardi, S., Hitomi, K., Maki, M., Carafoli, E. J. Biol. Chem. (1997) [Pubmed]
  3. Calpain-1 regulates Bax and subsequent Smac-dependent caspase-3 activation in neutrophil apoptosis. Altznauer, F., Conus, S., Cavalli, A., Folkers, G., Simon, H.U. J. Biol. Chem. (2004) [Pubmed]
  4. Expression of a calpastatin transgene slows muscle wasting and obviates changes in myosin isoform expression during murine muscle disuse. Tidball, J.G., Spencer, M.J. J. Physiol. (Lond.) (2002) [Pubmed]
  5. Molecular cloning and characterization of functional domains of a human testis-specific isoform of calpastatin. Li, S., Liang, Z.G., Wang, G.Y., Yavetz, B., Kim, E.D., Goldberg, E. Biol. Reprod. (2000) [Pubmed]
  6. Mutation analysis of the calpastatin gene (CAST) in patients with Alzheimer's disease. Nakayama, J., Yoshizawa, T., Yamamoto, N., Arinami, T. Neurosci. Lett. (2002) [Pubmed]
  7. The calpain system. Goll, D.E., Thompson, V.F., Li, H., Wei, W., Cong, J. Physiol. Rev. (2003) [Pubmed]
  8. Cytoskeletal regulation couples LFA-1 conformational changes to receptor lateral mobility and clustering. Cairo, C.W., Mirchev, R., Golan, D.E. Immunity (2006) [Pubmed]
  9. WIP is a chaperone for Wiskott-Aldrich syndrome protein (WASP). de la Fuente, M.A., Sasahara, Y., Calamito, M., Antón, I.M., Elkhal, A., Gallego, M.D., Suresh, K., Siminovitch, K., Ochs, H.D., Anderson, K.C., Rosen, F.S., Geha, R.S., Ramesh, N. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  10. Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. Zhu, D.M., Uckun, F.M. Clin. Cancer Res. (2000) [Pubmed]
  11. Inhibition of proteolytic activity of poliovirus and rhinovirus 2A proteinases by elastase-specific inhibitors. Molla, A., Hellen, C.U., Wimmer, E. J. Virol. (1993) [Pubmed]
  12. Biochemical interaction between Tamm-Horsfall glycoprotein and Ig light chains in the pathogenesis of cast nephropathy. Huang, Z.Q., Sanders, P.W. Lab. Invest. (1995) [Pubmed]
  13. Amelioration of retinal degeneration and proteolysis in acute ocular hypertensive rats by calpain inhibitor ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester. Oka, T., Walkup, R.D., Tamada, Y., Nakajima, E., Tochigi, A., Shearer, T.R., Azuma, M. Neuroscience (2006) [Pubmed]
  14. Calpains and calpastatin in SH-SY5Y neuroblastoma cells during retinoic acid-induced differentiation and neurite outgrowth: comparison with the human brain calpain system. Grynspan, F., Griffin, W.B., Mohan, P.S., Shea, T.B., Nixon, R.A. J. Neurosci. Res. (1997) [Pubmed]
  15. Characterization of a functional domain of human calpastatin. Uemori, T., Shimojo, T., Asada, K., Asano, T., Kimizuka, F., Kato, I., Maki, M., Hatanaka, M., Murachi, T., Hanzawa, H. Biochem. Biophys. Res. Commun. (1990) [Pubmed]
  16. Autoantibodies to calpastatin (an endogenous inhibitor for calcium-dependent neutral protease, calpain) in systemic rheumatic diseases. Mimori, T., Suganuma, K., Tanami, Y., Nojima, T., Matsumura, M., Fujii, T., Yoshizawa, T., Suzuki, K., Akizuki, M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  17. Increase in ultraviolet sensitivity by overexpression of calpastatin in ultraviolet-resistant UVr-1 cells derived from ultraviolet-sensitive human RSa cells. Hiwasa, T., Arase, Y., Kikuno, K., Hasegawa, R., Sugaya, S., Kita, K., Saido, T., Yamamori, H., Maki, M., Suzuki, N. Cell Death Differ. (2000) [Pubmed]
  18. Phosphorylation and subcellular distribution of calpastatin in human hematopoietic system cells. Adachi, Y., Ishida-Takahashi, A., Takahashi, C., Takano, E., Murachi, T., Hatanaka, M. J. Biol. Chem. (1991) [Pubmed]
  19. Calpain inhibition decreases the growth rate of mammalian cell colonies. Xu, Y., Mellgren, R.L. J. Biol. Chem. (2002) [Pubmed]
  20. Molecular diversity in amino-terminal domains of human calpastatin by exon skipping. Lee, W.J., Ma, H., Takano, E., Yang, H.Q., Hatanaka, M., Maki, M. J. Biol. Chem. (1992) [Pubmed]
  21. Improved posthypoxic recovery of synaptic transmission in gerbil neocortical slices treated with a calpain inhibitor. Hiramatsu, K., Kassell, N.F., Lee, K.S. Stroke (1993) [Pubmed]
  22. Calpastatin in erythrocytes of young and old individuals. Schwarz-Benmeir, N., Glaser, T., Barnoy, S., Kosower, N.S. Biochem. J. (1994) [Pubmed]
  23. Differential sensitivity of interleukin-1 alpha and -beta precursor proteins to cleavage by calpain, a calcium-dependent protease. Kavita, U., Mizel, S.B. J. Biol. Chem. (1995) [Pubmed]
  24. AlphaPIX associates with calpain 4, the small subunit of calpain, and has a dual role in integrin-mediated cell spreading. Rosenberger, G., Gal, A., Kutsche, K. J. Biol. Chem. (2005) [Pubmed]
  25. Association of the calpain/calpastatin network with subcellular organelles. Hood, J.L., Logan, B.B., Sinai, A.P., Brooks, W.H., Roszman, T.L. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  26. Requirement of different subdomains of calpastatin for calpain inhibition and for binding to calmodulin-like domains. Ma, H., Yang, H.Q., Takano, E., Lee, W.J., Hatanaka, M., Maki, M. J. Biochem. (1993) [Pubmed]
  27. Cleavage of nonmuscle myosin heavy chain-A during apoptosis in human Jurkat T cells. Kato, M., Fukuda, H., Nonaka, T., Imajoh-Ohmi, S. J. Biochem. (2005) [Pubmed]
  28. Calpain inhibitor causes accumulation of ubiquitinated P-glycoprotein at the cell surface: possible role of calpain in P-glycoprotein turnover. Ohkawa, K., Asakura, T., Takada, K., Sawai, T., Hashizume, Y., Okawa, Y., Yanaihara, N. Int. J. Oncol. (1999) [Pubmed]
  29. Inflammatory cytokines induced down-regulation of m-calpain mRNA expression in fibroblastic synoviocytes from patients with osteoarthritis and rheumatoid arthritis. Ishikawa, H., Nakagawa, Y., Shimizu, K., Nishihara, H., Matsusue, Y., Nakamura, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  30. Extracellular matrix enhances heregulin-dependent BRCA1 phosphorylation and suppresses BRCA1 expression through its C terminus. Miralem, T., Avraham, H.K. Mol. Cell. Biol. (2003) [Pubmed]
  31. Inhibition of p21/Waf1/Cip1/Sdi1 expression by hepatitis C virus core protein. Yoshida, I., Oka, K., Hidajat, R., Nagano-Fujii, M., Ishido, S., Hotta, H. Microbiol. Immunol. (2001) [Pubmed]
  32. Mu-calpain activation in beta-lapachone-mediated apoptosis. Tagliarino, C., Pink, J.J., Reinicke, K.E., Simmers, S.M., Wuerzberger-Davis, S.M., Boothman, D.A. Cancer Biol. Ther. (2003) [Pubmed]
  33. Integrin alpha2-mediated ERK and calpain activation play a critical role in cell adhesion and motility via focal adhesion kinase signaling: identification of a novel signaling pathway. Sawhney, R.S., Cookson, M.M., Omar, Y., Hauser, J., Brattain, M.G. J. Biol. Chem. (2006) [Pubmed]
  34. Calcium-activated neutral proteinase (CANP; calpain) activity in Schwann cells: immunofluorescence localization and compartmentation of mu- and mCANP. Banik, N.L., DeVries, G.H., Neuberger, T., Russell, T., Chakrabarti, A.K., Hogan, E.L. J. Neurosci. Res. (1991) [Pubmed]
  35. A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. Shields, D.C., Schaecher, K.E., Saido, T.C., Banik, N.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  36. Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation. Han, Y., Weinman, S., Boldogh, I., Walker, R.K., Brasier, A.R. J. Biol. Chem. (1999) [Pubmed]
  37. Identification of mu-, m-calpains and calpastatin and capture of mu-calpain activation in endothelial cells. Fujitani, K., Kambayashi, J., Sakon, M., Ohmi, S.I., Kawashima, S., Yukawa, M., Yano, Y., Miyoshi, H., Ikeda, M., Shinoki, N., Monden, M. J. Cell. Biochem. (1997) [Pubmed]
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