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Gene Review

Capn1  -  calpain 1

Mus musculus

Synonyms: CANP 1, Calcium-activated neutral proteinase 1, Calpain mu-type, Calpain-1 catalytic subunit, Calpain-1 large subunit, ...
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Disease relevance of Capn1

  • Here, we identify two calpain cleavage sites in Htt and show that mutation of these sites renders the polyQ expanded Htt less susceptible to proteolysis and aggregation, resulting in decreased toxicity in an in vitro cell culture model [1].
  • Calpain activation and secretion promote glomerular injury in experimental glomerulonephritis: evidence from calpastatin-transgenic mice [2].
  • Wild-type mice that were subjected to anti-glomerular basement membrane nephritis exhibited elevated levels of calpain activity in kidney cortex at the heterologous phase of the disease [2].
  • There also was a reduction in nephrin disappearance from the surface of podocytes, indicating that calpain activity would enhance proteinuria by affecting nephrin expression [2].
  • Taken together, these results strongly suggest that epigenetic activation of calpain plays an important role in the invasion of human prostate cancer and that it can be targeted to reduce tumor progression [3].

Psychiatry related information on Capn1


High impact information on Capn1


Chemical compound and disease context of Capn1


Biological context of Capn1


Anatomical context of Capn1


Associations of Capn1 with chemical compounds

  • This PIP(2)-binding capacity resided in domain III of calpain, which presents a putative C2-like domain [15].
  • Enzymatic inhibition of calpain by calpeptin precluded AIF release, demonstrating that proteolytic activity was required for release [20].
  • Calpain Is Required for the Rapid, Calcium-dependent Repair of Wounded Plasma Membrane [21].
  • Capn4(-/-) MEFs displayed resistance to puromycin, camptothecin, etoposide, hydrogen peroxide, ultraviolet light, and serum starvation, which was consistent with pro-apoptotic roles for calpain [22].
  • Calpain, a calcium-activated cysteine protease, has been shown to participate in the development of the inflammatory process [2].

Physical interactions of Capn1


Enzymatic interactions of Capn1

  • Both precursor and mature forms of recombinant AIF were cleaved near the amino terminus by calpain I in vitro [20].
  • The structural requirements of PKC were then examined using a calpain-cleaved active fragment of nPKC delta [26].
  • Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice [27].

Regulatory relationships of Capn1

  • Because elevated intracellular calcium is one of the most ubiquitous features of neuronal cell death, this study tested the hypothesis that cleavage of AIF by the calcium-activated protease calpain mediates its release from mitochondria [20].
  • With differential ligand-induced internalization and trafficking-restricted receptor variants, we find that calpain activity is triggered only by plasma membrane-restricted activated EGFR, not by internalized (although still active) EGFR [28].
  • The association of calpain with the plasma membrane was verified by immunoblots of isolated sarcolemmal membrane from adult mdx and control muscle which showed calpain present predominantly in the cytosol along with some membrane association [29].
  • Calpain inhibitors suppressed NF-kappaB activation via inhibition of the cleavage of inhibitor of NF-kappaB(IkappaBalpha)in RAW 264.7 cells [30].
  • In addition, we showed that activation of cellular calpains by Ca2+ ionophore treatment reduces utrophin protein levels in muscle cells and that calpain inhibition prevents this Ca2+ -induced reduction in utrophin levels [31].

Other interactions of Capn1

  • Taken together, these results define a novel mechanism of AIF release involving calpain processing and identify a potential molecular checkpoint for cytoprotective interventions [20].
  • Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway [32].
  • In contrast, capn4(-/-) MEFs were more susceptible to staurosporine (STS) and tumor necrosis factor alpha-induced cell death, which provided evidence for anti-apoptotic signaling roles for calpain [22].
  • Interestingly, calpain-1, -5, -7, and -10 localize to the cytoplasm and the nucleus, whereas the activated forms of calpain-7 and -10 are found only in the nucleus [1].
  • Recent studies have implicated both extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase and calpain (EC in these processes, but it is uncertain whether these are two distinct pathways acting on different modes of motility [32].
  • Together, our results demonstrate that PTP1B is a physiological target of calpain-1 and suggest that a similar mechanism may regulate calpain-1-mediated tyrosine dephosphorylation in other cells [33].

Analytical, diagnostic and therapeutic context of Capn1


  1. Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. Gafni, J., Hermel, E., Young, J.E., Wellington, C.L., Hayden, M.R., Ellerby, L.M. J. Biol. Chem. (2004) [Pubmed]
  2. Calpain activation and secretion promote glomerular injury in experimental glomerulonephritis: evidence from calpastatin-transgenic mice. Peltier, J., Bellocq, A., Perez, J., Doublier, S., Dubois, Y.C., Haymann, J.P., Camussi, G., Baud, L. J. Am. Soc. Nephrol. (2006) [Pubmed]
  3. Calpain-2 as a target for limiting prostate cancer invasion. Mamoune, A., Luo, J.H., Lauffenburger, D.A., Wells, A. Cancer Res. (2003) [Pubmed]
  4. Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Kim, Y.J., Yi, Y., Sapp, E., Wang, Y., Cuiffo, B., Kegel, K.B., Qin, Z.H., Aronin, N., DiFiglia, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  5. Calpain inhibitors: a treatment for Alzheimer's disease. Di Rosa, G., Odrijin, T., Nixon, R.A., Arancio, O. J. Mol. Neurosci. (2002) [Pubmed]
  6. Neurotoxicity induces cleavage of p35 to p25 by calpain. Lee, M.S., Kwon, Y.T., Li, M., Peng, J., Friedlander, R.M., Tsai, L.H. Nature (2000) [Pubmed]
  7. Transplanted long-term cultured pre-BI cells expressing calpastatin are resistant to B cell receptor-induced apoptosis. Ruiz-Vela, A., Serrano, F., González, M.A., Abad, J.L., Bernad, A., Maki, M., Martínez-A, C. J. Exp. Med. (2001) [Pubmed]
  8. MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. Cuevas, B.D., Abell, A.N., Witowsky, J.A., Yujiri, T., Johnson, N.L., Kesavan, K., Ware, M., Jones, P.L., Weed, S.A., DeBiasi, R.L., Oka, Y., Tyler, K.L., Johnson, G.L. EMBO J. (2003) [Pubmed]
  9. Platelet factor XIII and calpain negatively regulate integrin alphaIIbbeta3 adhesive function and thrombus growth. Kulkarni, S., Jackson, S.P. J. Biol. Chem. (2004) [Pubmed]
  10. Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. McDonald, M.C., Mota-Filipe, H., Paul, A., Cuzzocrea, S., Abdelrahman, M., Harwood, S., Plevin, R., Chatterjee, P.K., Yaqoob, M.M., Thiemermann, C. FASEB J. (2001) [Pubmed]
  11. Adenoviral gene transfer of a mutant surfactant enzyme ameliorates pseudomonas-induced lung injury. Zhou, J., Wu, Y., Henderson, F., McCoy, D.M., Salome, R.G., McGowan, S.E., Mallampalli, R.K. Gene Ther. (2006) [Pubmed]
  12. Selective Deletion of the NH(2)-Terminal Variable Region of Cardiac Troponin T in Ischemia Reperfusion by Myofibril-Associated mu-Calpain Cleavage. Zhang, Z., Biesiadecki, B.J., Jin, J.P. Biochemistry (2006) [Pubmed]
  13. Buthionine sulfoximine induced cataracts in mice contain insolubilized crystallins with calpain II cleavage sites. David, L.L., Calvin, H.I., Fu, S.C. Exp. Eye Res. (1994) [Pubmed]
  14. Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. Spencer, M.J., Mellgren, R.L. Hum. Mol. Genet. (2002) [Pubmed]
  15. Spatial localization of m-calpain to the plasma membrane by phosphoinositide biphosphate binding during epidermal growth factor receptor-mediated activation. Shao, H., Chou, J., Baty, C.J., Burke, N.A., Watkins, S.C., Stolz, D.B., Wells, A. Mol. Cell. Biol. (2006) [Pubmed]
  16. Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division. Arthur, J.S., Elce, J.S., Hegadorn, C., Williams, K., Greer, P.A. Mol. Cell. Biol. (2000) [Pubmed]
  17. Group B Streptococcus induces macrophage apoptosis by calpain activation. Fettucciari, K., Fetriconi, I., Mannucci, R., Nicoletti, I., Bartoli, A., Coaccioli, S., Marconi, P. J. Immunol. (2006) [Pubmed]
  18. Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts. Dourdin, N., Bhatt, A.K., Dutt, P., Greer, P.A., Arthur, J.S., Elce, J.S., Huttenlocher, A. J. Biol. Chem. (2001) [Pubmed]
  19. Calpain system regulates muscle mass and glucose transporter GLUT4 turnover. Otani, K., Han, D.H., Ford, E.L., Garcia-Roves, P.M., Ye, H., Horikawa, Y., Bell, G.I., Holloszy, J.O., Polonsky, K.S. J. Biol. Chem. (2004) [Pubmed]
  20. Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. Polster, B.M., Basañez, G., Etxebarria, A., Hardwick, J.M., Nicholls, D.G. J. Biol. Chem. (2005) [Pubmed]
  21. Calpain Is Required for the Rapid, Calcium-dependent Repair of Wounded Plasma Membrane. Mellgren, R.L., Zhang, W., Miyake, K., McNeil, P.L. J. Biol. Chem. (2007) [Pubmed]
  22. Ubiquitous calpains promote both apoptosis and survival signals in response to different cell death stimuli. Tan, Y., Wu, C., De Veyra, T., Greer, P.A. J. Biol. Chem. (2006) [Pubmed]
  23. Calpain, an upstream regulator of thymocyte apoptosis. Squier, M.K., Cohen, J.J. J. Immunol. (1997) [Pubmed]
  24. Somatostatin increases glucocorticoid binding and signaling in macrophages by blocking the calpain-specific cleavage of Hsp 90. Bellocq, A., Doublier, S., Suberville, S., Perez, J., Escoubet, B., Fouqueray, B., Puyol, D.R., Baud, L. J. Biol. Chem. (1999) [Pubmed]
  25. Properties of erythrocyte membrane binding and autolytic activation of calcium-activated neutral protease. Inomata, M., Hayashi, M., Nakamura, M., Saito, Y., Kawashima, S. J. Biol. Chem. (1989) [Pubmed]
  26. Specificity of the high affinity interaction of protein kinase C with a physiological substrate, myristoylated alanine-rich protein kinase C substrate. Fujise, A., Mizuno, K., Ueda, Y., Osada, S., Hirai, S., Takayanagi, A., Shimizu, N., Owada, M.K., Nakajima, H., Ohno, S. J. Biol. Chem. (1994) [Pubmed]
  27. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease. Calon, F., Lim, G.P., Morihara, T., Yang, F., Ubeda, O., Salem, N., Frautschy, S.A., Cole, G.M. Eur. J. Neurosci. (2005) [Pubmed]
  28. Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling. Glading, A., Uberall, F., Keyse, S.M., Lauffenburger, D.A., Wells, A. J. Biol. Chem. (2001) [Pubmed]
  29. Calpain translocation during muscle fiber necrosis and regeneration in dystrophin-deficient mice. Spencer, M.J., Tidball, J.G. Exp. Cell Res. (1996) [Pubmed]
  30. mu-Calpain regulates receptor activator of NF-kappaB ligand (RANKL)-supported osteoclastogenesis via NF-kappaB activation in RAW 264.7 cells. Lee, F.Y., Kim, D.W., Karmin, J.A., Hong, D., Chang, S.S., Fujisawa, M., Takayanagi, H., Bigliani, L.U., Blaine, T.A., Lee, H.J. J. Biol. Chem. (2005) [Pubmed]
  31. Utrophin is a calpain substrate in muscle cells. Courdier-Fruh, I., Briguet, A. Muscle Nerve (2006) [Pubmed]
  32. Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway. Glading, A., Chang, P., Lauffenburger, D.A., Wells, A. J. Biol. Chem. (2000) [Pubmed]
  33. Double knockouts reveal that protein tyrosine phosphatase 1B is a physiological target of calpain-1 in platelets. Kuchay, S.M., Kim, N., Grunz, E.A., Fay, W.P., Chishti, A.H. Mol. Cell. Biol. (2007) [Pubmed]
  34. Kainate induces AKT, ERK and cdk5/GSK3beta pathway deregulation, phosphorylates tau protein in mouse hippocampus. Crespo-Biel, N., Canudas, A.M., Camins, A., Pallàs, M. Neurochem. Int. (2007) [Pubmed]
  35. Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. Azam, M., Andrabi, S.S., Sahr, K.E., Kamath, L., Kuliopulos, A., Chishti, A.H. Mol. Cell. Biol. (2001) [Pubmed]
  36. Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells. Gomperts, B.N., Gong-Cooper, X., Hackett, B.P. J. Cell. Sci. (2004) [Pubmed]
  37. Activation of calpains, calpastatin and spectrin cleavage in the brain during the pathology of fatal murine cerebral malaria. Shukla, M., Rajgopal, Y., Babu, P.P. Neurochem. Int. (2006) [Pubmed]
  38. Regional differences in gene expression for calcium activated neutral proteases (calpains) and their endogenous inhibitor calpastatin in mouse brain and spinal cord. Li, J., Grynspan, F., Berman, S., Nixon, R., Bursztajn, S. J. Neurobiol. (1996) [Pubmed]
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