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The calpain system and cancer

Key Points

  • The calpains are a family of cysteine proteases that catalyse the controlled proteolysis of a large number of specific substrates.

  • Although the calpain family consists of more than ten members, μ-calpain and m-calpain are the most commonly described and are ubiquitously expressed.

  • Calpastatin is the endogenous inhibitor of μ-calpain and m-calpain and it has multiple isoforms and splice variants.

  • Calpain is linked to cancer and a number of other disease states, including limb-girdle muscular dystrophy type 2A (LGMD2A) and neurodegeneration.

  • Calpain activity is linked to cellular migration through the proteolysis of focal adhesion proteins, such as focal adhesion kinase and talin.

  • Calpain is linked to cell survival through the cleavage of inhibitors of nuclear factor-κB (IκB).

  • Calpain is linked to apoptosis through cleavage of BCL-2 family members, caspases and apoptosis-inducing factor.

  • Expression of calpain and calpastatin has been linked to tumour progression and response to therapies.

Abstract

The calpains are a conserved family of cysteine proteinases that catalyse the controlled proteolysis of many specific substrates. Calpain activity is implicated in several fundamental physiological processes, including cytoskeletal remodelling, cellular signalling, apoptosis and cell survival. Calpain expression is altered during tumorigenesis, and the proteolysis of numerous substrates, such as inhibitors of nuclear factor-κB (IκB), focal adhesion proteins (including, focal adhesion kinase and talin) and proto-oncogenes (for example, MYC), has been implicated in tumour pathogenesis. Recent evidence indicates that the increased expression of certain family members might influence the response to cancer therapies, providing justification for the development of novel calpain inhibitors.

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Figure 1: Schematic structure of μ-calpain heterodimer and calpain family members.
Figure 2: Schematic structure of calpastatin.
Figure 3: Calpain and migration.
Figure 4: Calpain and apoptosis.
Figure 5: Chemical structures selected from distinct classes of calpain inhibitors.

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References

  1. Guroff, G. A neutral, calcium-activated proteinase from the soluble fraction of rat brain. J. Biol. Chem. 239, 149–155 (1964).

    CAS  PubMed  Google Scholar 

  2. Croall, D. E. & DeMartino, G. N. Calcium-activated neutral protease (calpain) system: structure, function, and regulation. Physiol. Rev. 71, 813–847 (1991).

    CAS  PubMed  Google Scholar 

  3. Sorimachi, H., Hata, S. & Ono, Y. Expanding members and roles of the calpain superfamily and their genetically modified animals. Exp. Anim. 59, 549–566 (2010).

    CAS  PubMed  Google Scholar 

  4. Goll, D. E., Thompson, V. F., Li, H., Wei, W. & Cong, J. The calpain system. Physiol. Rev. 83, 731–801 (2003).

    CAS  PubMed  Google Scholar 

  5. Dayton, W. R., Schollmeyer, J. V., Lepley, R. A. & Cortes, L. R. A calcium-activated protease possibly involved in myofibrillar protein turnover. Isolation of a low-calcium-requiring form of the protease. Biochim. Biophys. Acta 659, 48–61 (1981).

    CAS  PubMed  Google Scholar 

  6. Mellgren, R. L. Canine cardiac calcium-dependent proteases: resolution of two forms with different requirements for calcium. FEBS Lett. 109, 129–133 (1980).

    CAS  PubMed  Google Scholar 

  7. Inomata, M., Hayashi, M., Nakamura, M., Imahori, K. & Kawashima, S. Purification and characterization of a calcium-activated neutral protease from rabbit skeletal muscle which requires calcium ions of microM order concentration. J. Biochem. 93, 291–294 (1983).

    CAS  PubMed  Google Scholar 

  8. Cong, J., Goll, D. E., Peterson, A. M. & Kapprell, H. P. The role of autolysis in activity of the Ca2+-dependent proteinases (mu-calpain and m-calpain). J. Biol. Chem. 264, 10096–10103 (1989).

    CAS  PubMed  Google Scholar 

  9. Edmunds, T., Nagainis, P. A., Sathe, S. K., Thompson, V. F. & Goll, D. E. Comparison of the autolyzed and unautolyzed forms of mu- and m-calpain from bovine skeletal muscle. Biochim. Biophys. Acta 1077, 197–208 (1991).

    CAS  PubMed  Google Scholar 

  10. Coolican, S. A. & Hathaway, D. R. Effect of L-α-phosphatidylinositol on a vascular smooth muscle Ca2+-dependent protease. Reduction of the Ca2+ requirement for autolysis. J. Biol. Chem. 259, 11627–11630 (1984).

    CAS  PubMed  Google Scholar 

  11. Imajoh, S., Kawasaki, H. & Suzuki, K. The amino-terminal hydrophobic region of the small subunit of calcium-activated neutral protease (CANP) is essential for its activation by phosphatidylinositol. J. Biochem. 99, 1281–1284 (1986).

    CAS  PubMed  Google Scholar 

  12. Saido, T. C., Mizuno, K. & Suzuki, K. Proteolysis of protein kinase C by calpain: effect of acidic phospholipids. Biomed. Biochim. Acta 50, 485–489 (1991).

    CAS  PubMed  Google Scholar 

  13. Saido, T. C., Shibata, M., Takenawa, T., Murofushi, H. & Suzuki, K. Positive regulation of mu-calpain action by polyphosphoinositides. J. Biol. Chem. 267, 24585–24590 (1992).

    CAS  PubMed  Google Scholar 

  14. Aoki, K. et al. Complete amino acid sequence of the large subunit of the low-Ca2+-requiring form of human Ca2+-activated neutral protease (muCANP) deduced from its cDNA sequence. FEBS Lett. 205, 313–317 (1986).

    CAS  PubMed  Google Scholar 

  15. Imajoh, S. et al. Molecular cloning of the cDNA for the large subunit of the high-Ca2+-requiring form of human Ca2+-activated neutral protease. Biochemistry 27, 8122–8128 (1988).

    CAS  PubMed  Google Scholar 

  16. Ohno, S. et al. Evolutionary origin of a calcium-dependent protease by fusion of genes for a thiol protease and a calcium-binding protein? Nature 312, 566–570 (1984).

    CAS  PubMed  Google Scholar 

  17. Kawasaki, H., Imajoh, S., Kawashima, S., Hayashi, H. & Suzuki, K. The small subunits of calcium dependent proteases with different calcium sensitivities are identical. J. Biochem. 99, 1525–1532 (1986).

    CAS  PubMed  Google Scholar 

  18. Ohno, S., Emori, Y. & Suzuki, K. Nucleotide sequence of a cDNA coding for the small subunit of human calcium-dependent protease. Nucleic Acids Res. 14, 5559 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hosfield, C. M., Elce, J. S., Davies, P. L. & Jia, Z. Crystal structure of calpain reveals the structural basis for Ca2+-dependent protease activity and a novel mode of enzyme activation. EMBO J. 18, 6880–6889 (1999). This work showed the calcium-free structure of calpain, which can be used to explain enzymatic inactivity in the absence of calcium.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Strobl, S. et al. The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proc. Natl Acad. Sci. USA 97, 588–592 (2000). This study investigated the structure of calpain without calcium, and describes the formation of a catalytic centre.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hanna, R. A., Campbell, R. L. & Davies, P. L. Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature 456, 409–412 (2008). This structural study shows the potent nature of specific calpastatin inhibition of up to four calpain molecules and the calcium-mediated conformational change.

    CAS  PubMed  Google Scholar 

  22. Moldoveanu, T., Gehring, K. & Green, D. R. Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains. Nature 456, 404–408 (2008). This structural study shows the calcium-mediated conformational changes that are required for calpastatin inhibition of calpain.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Minami, Y., Emori, Y., Kawasaki, H. & Suzuki, K. E-F hand structure-domain of calcium-activated neutral protease (CANP) can bind Ca2+ ions. J. Biochem. 101, 889–895 (1987).

    CAS  PubMed  Google Scholar 

  24. Imajoh, S., Kawasaki, H. & Suzuki, K. The COOH-terminal E-F hand structure of calcium-activated neutral protease (CANP) is important for the association of subunits and resulting proteolytic activity. J. Biochem. 101, 447–452 (1987).

    CAS  PubMed  Google Scholar 

  25. Blanchard, H. et al. Structure of a calpain Ca2+-binding domain reveals a novel EF-hand and Ca2+-induced conformational changes. Nature Struct. Biol. 4, 532–538 (1997).

    CAS  PubMed  Google Scholar 

  26. Azam, M. et al. Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. Mol. Cell. Biol. 21, 2213–2220 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Dutt, P. et al. m-Calpain is required for preimplantation embryonic development in mice. BMC Dev. Biol. 6, 3 (2006).

    PubMed  PubMed Central  Google Scholar 

  28. Arthur, J. S., Elce, J. S., Hegadorn, C., Williams, K. & Greer, P. A. Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division. Mol. Cell. Biol. 20, 4474–4481 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Imajoh, S., Kawasaki, H. & Suzuki, K. Limited autolysis of calcium-activated neutral protease (CANP): reduction of the Ca2+-requirement is due to the NH2-terminal processing of the large subunit. J. Biochem. 100, 633–642 (1986).

    CAS  PubMed  Google Scholar 

  30. Suzuki, K., Tsuji, S., Kubota, S., Kimura, Y. & Imahori, K. Limited autolysis of Ca2+-activated neutral protease (CANP) changes its sensitivity to Ca2+ ions. J. Biochem. 90, 275–278 (1981).

    CAS  PubMed  Google Scholar 

  31. Pontremoli, S. et al. An endogenous activator of the Ca2+-dependent proteinase of human neutrophils that increases its affinity for Ca2+. Proc. Natl Acad. Sci. USA 85, 1740–1743 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Pontremoli, S. et al. Identification of an endogenous activator of calpain in rat skeletal muscle. Biochem. Biophys. Res. Commun. 171, 569–574 (1990).

    CAS  PubMed  Google Scholar 

  33. Salamino, F. et al. Site-directed activation of calpain is promoted by a membrane-associated natural activator protein. Biochem. J. 290, 191–197 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Melloni, E., Michetti, M., Salamino, F. & Pontremoli, S. Molecular and functional properties of a calpain activator protein specific for mu-isoforms. J. Biol. Chem. 273, 12827–12831 (1998).

    CAS  PubMed  Google Scholar 

  35. Xu, L. & Deng, X. Protein kinase Ciota promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of micro- and m-calpains. J. Biol. Chem. 281, 4457–4466 (2006).

    CAS  PubMed  Google Scholar 

  36. Glading, A., Uberall, F., Keyse, S. M., Lauffenburger, D. A. & Wells, A. Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling. J. Biol. Chem. 276, 23341–23348 (2001). This study demonstrated that m-calpain can be activated by ERK during EGFR signalling.

    CAS  PubMed  Google Scholar 

  37. Smith, S. D., Jia, Z., Huynh, K. K., Wells, A. & Elce, J. S. Glutamate substitutions at a PKA consensus site are consistent with inactivation of calpain by phosphorylation. FEBS Lett. 542, 115–118 (2003).

    CAS  PubMed  Google Scholar 

  38. Shiraha, H., Glading, A., Chou, J., Jia, Z. & Wells, A. Activation of m-calpain (calpain II) by epidermal growth factor is limited by protein kinase A phosphorylation of m-calpain. Mol. Cell. Biol. 22, 2716–2727 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Leloup, L. et al. m-Calpain activation is regulated by its membrane localization and by its binding to phosphatidylinositol 4, 5-bisphosphate. J. Biol. Chem. 285, 33549–33566 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Shao, H. et al. Spatial localization of m-calpain to the plasma membrane by phosphoinositide biphosphate binding during epidermal growth factor receptor-mediated activation. Mol. Cell. Biol. 26, 5481–5496 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Goudenege, S., Poussard, S., Dulong, S. & Cottin, P. Biologically active milli-calpain associated with caveolae is involved in a spatially compartmentalised signalling involving protein kinase C α and myristoylated alanine-rich C-kinase substrate (MARCKS). Int. J. Biochem. Cell Biol. 37, 1900–1910 (2005).

    CAS  PubMed  Google Scholar 

  42. Kifor, O., Kifor, I., Moore, F. D. Jr, Butters, R. R. Jr & Brown, E. M. m-Calpain colocalizes with the calcium-sensing receptor (CaR) in caveolae in parathyroid cells and participates in degradation of the CaR. J. Biol. Chem. 278, 31167–31176 (2003).

    CAS  PubMed  Google Scholar 

  43. Garcia, M., Bondada, V. & Geddes, J. W. Mitochondrial localization of mu-calpain. Biochem. Biophys. Res. Commun. 338, 1241–1247 (2005).

    CAS  PubMed  Google Scholar 

  44. Badugu, R., Garcia, M., Bondada, V., Joshi, A. & Geddes, J. W. N. terminus of calpain 1 is a mitochondrial targeting sequence. J. Biol. Chem. 283, 3409–3417 (2008).

    CAS  PubMed  Google Scholar 

  45. Kar, P., Chakraborti, T., Samanta, K. & Chakraborti, S. Submitochondrial localization of associated mu-calpain and calpastatin. Arch. Biochem. Biophys. 470, 176–186 (2008).

    CAS  PubMed  Google Scholar 

  46. Wendt, A., Thompson, V. F. & Goll, D. E. Interaction of calpastatin with calpain: a review. Biol. Chem. 385, 465–472 (2004).

    CAS  PubMed  Google Scholar 

  47. Hanna, R. A., Garcia-Diaz, B. E. & Davies, P. L. Calpastatin simultaneously binds four calpains with different kinetic constants. FEBS Lett. 581, 2894–2898 (2007).

    CAS  PubMed  Google Scholar 

  48. Kapprell, H. P. & Goll, D. E. Effect of Ca2+ on binding of the calpains to calpastatin. J. Biol. Chem. 264, 17888–17896 (1989).

    CAS  PubMed  Google Scholar 

  49. Averna, M. et al. Changes in calpastatin localization and expression during calpain activation: a new mechanism for the regulation of intracellular Ca2+-dependent proteolysis. Cell. Mol. Life Sci. 60, 2669–2678 (2003).

    CAS  PubMed  Google Scholar 

  50. De Tullio, R., Sparatore, B., Salamino, F., Melloni, E. & Pontremoli, S. Rat brain contains multiple mRNAs for calpastatin. FEBS Lett. 422, 113–117 (1998).

    CAS  PubMed  Google Scholar 

  51. Parr, T. et al. Expression of calpastatin isoforms in muscle and functionality of multiple calpastatin promoters. Arch. Biochem. Biophys. 427, 8–15 (2004).

    CAS  PubMed  Google Scholar 

  52. Parr, T., Sensky, P. L., Bardsley, R. G. & Buttery, P. J. Calpastatin expression in porcine cardiac and skeletal muscle and partial gene structure. Arch. Biochem. Biophys. 395, 1–13 (2001).

    CAS  PubMed  Google Scholar 

  53. Raynaud, P., Jayat-Vignoles, C., Laforet, M. P., Leveziel, H. & Amarger, V. Four promoters direct expression of the calpastatin gene. Arch. Biochem. Biophys. 437, 69–77 (2005).

    CAS  PubMed  Google Scholar 

  54. Takano, J., Kawamura, T., Murase, M., Hitomi, K. & Maki, M. Structure of mouse calpastatin isoforms: implications of species-common and species-specific alternative splicing. Biochem. Biophys. Res. Commun. 260, 339–345 (1999).

    CAS  PubMed  Google Scholar 

  55. Takano, J., Watanabe, M., Hitomi, K. & Maki, M. Four types of calpastatin isoforms with distinct amino-terminal sequences are specified by alternative first exons and differentially expressed in mouse tissues. J. Biochem. 128, 83–92 (2000).

    CAS  PubMed  Google Scholar 

  56. Cong, M., Thompson, V. F., Goll, D. E. & Antin, P. B. The bovine calpastatin gene promoter and a new N-terminal region of the protein are targets for cAMP-dependent protein kinase activity. J. Biol. Chem. 273, 660–666 (1998).

    CAS  PubMed  Google Scholar 

  57. Sensky, P. L. et al. Effect of anabolic agents on calpastatin promoters in porcine skeletal muscle and their responsiveness to cyclic adenosine monophosphate- and calcium-related stimuli. J. Anim. Sci. 84, 2973–2982 (2006).

    CAS  PubMed  Google Scholar 

  58. Geesink, G. H., Nonneman, D. & Koohmaraie, M. An improved purification protocol for heart and skeletal muscle calpastatin reveals two isoforms resulting from alternative splicing. Arch. Biochem. Biophys. 356, 19–24 (1998).

    CAS  PubMed  Google Scholar 

  59. Raynaud, P. et al. Correlation between bovine calpastatin mRNA transcripts and protein isoforms. Arch. Biochem. Biophys. 440, 46–53 (2005).

    CAS  PubMed  Google Scholar 

  60. De Tullio, R. et al. Multiple rat brain calpastatin forms are produced by distinct starting points and alternative splicing of the N-terminal exons. Arch. Biochem. Biophys. 465, 148–156 (2007).

    CAS  PubMed  Google Scholar 

  61. De Tullio, R. et al. Involvement of exon 6-mediated calpastatin intracellular movements in the modulation of calpain activation. Biochim. Biophys. Acta 1790, 182–187 (2009).

    CAS  PubMed  Google Scholar 

  62. Lee, W. J. et al. Molecular diversity in amino-terminal domains of human calpastatin by exon skipping. J. Biol. Chem. 267, 8437–8442 (1992). This work described the exon skipping that occurs in calpastatin resulting in a large number of variants.

    CAS  PubMed  Google Scholar 

  63. Minobe, E. et al. A region of calpastatin domain L that reprimes cardiac L-type Ca2+ channels. Biochem. Biophys. Res. Commun. 348, 288–294 (2006).

    CAS  PubMed  Google Scholar 

  64. Averna, M. et al. Changes in intracellular calpastatin localization are mediated by reversible phosphorylation. Biochem. J. 354, 25–30 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Averna, M. et al. Age-dependent degradation of calpastatin in kidney of hypertensive rats. J. Biol. Chem. 276, 38426–38432 (2001).

    CAS  PubMed  Google Scholar 

  66. Parr, T., Sensky, P. L., Arnold, M. K., Bardsley, R. G. & Buttery, P. J. Effects of epinephrine infusion on expression of calpastatin in porcine cardiac and skeletal muscle. Arch. Biochem. Biophys. 374, 299–305 (2000).

    CAS  PubMed  Google Scholar 

  67. Salamino, F. et al. Modulation of rat brain calpastatin efficiency by post-translational modifications. FEBS Lett. 412, 433–438 (1997).

    CAS  PubMed  Google Scholar 

  68. Tullio, R. D. et al. Changes in intracellular localization of calpastatin during calpain activation. Biochem. J. 343, 467–472 (1999).

    PubMed  PubMed Central  Google Scholar 

  69. Kimura, Y. et al. The involvement of calpain-dependent proteolysis of the tumor suppressor NF2 (merlin) in schwannomas and meningiomas. Nature Med. 4, 915–922 (1998).

    CAS  PubMed  Google Scholar 

  70. Braun, C. et al. Expression of calpain I messenger RNA in human renal cell carcinoma: correlation with lymph node metastasis and histological type. Int. J. Cancer 84, 6–9 (1999).

    CAS  PubMed  Google Scholar 

  71. Lakshmikuttyamma, A., Selvakumar, P., Kanthan, R., Kanthan, S. C. & Sharma, R. K. Overexpression of m-calpain in human colorectal adenocarcinomas. Cancer Epidemiol. Biomarkers Prev. 13, 1604–1609 (2004).

    CAS  PubMed  Google Scholar 

  72. Reichrath, J. et al. Different expression patterns of calpain isozymes 1 and 2 (CAPN1 and 2) in squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) of human skin. J. Pathol. 199, 509–516 (2003).

    CAS  PubMed  Google Scholar 

  73. Mamoune, A., Luo, J. H., Lauffenburger, D. A. & Wells, A. Calpain-2 as a target for limiting prostate cancer invasion. Cancer Res. 63, 4632–4640 (2003).

    CAS  PubMed  Google Scholar 

  74. Rios-Doria, J. et al. The role of calpain in the proteolytic cleavage of E-cadherin in prostate and mammary epithelial cells. J. Biol. Chem. 278, 1372–1379 (2003).

    CAS  PubMed  Google Scholar 

  75. Salehin, D. et al. Immunhistochemical analysis for expression of calpain 1, calpain 2 and calpastatin in endometrial cancer. Anticancer Res. 30, 2837–2843 (2010).

    CAS  PubMed  Google Scholar 

  76. Lee, S. J. et al. Increased expression of calpain 6 in uterine sarcomas and carcinosarcomas: an immunohistochemical analysis. Int. J. Gynecol. Cancer 17, 248–253 (2007).

    PubMed  Google Scholar 

  77. Lee, S. J., Kim, B. G., Choi, Y. L. & Lee, J. W. Increased expression of calpain 6 during the progression of uterine cervical neoplasia: immunohistochemical analysis. Oncol. Rep. 19, 859–863 (2008).

    PubMed  Google Scholar 

  78. Moretti, D. et al. Novel variants of muscle calpain 3 identified in human melanoma cells: cisplatin-induced changes in vitro and differential expression in melanocytic lesions. Carcinogenesis 30, 960–967 (2009).

    CAS  PubMed  Google Scholar 

  79. Yoshikawa, Y., Mukai, H., Hino, F., Asada, K. & Kato, I. Isolation of two novel genes, down-regulated in gastric cancer. Jpn J. Cancer Res. 91, 459–463 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Moreno-Luna, R. et al. Calpain 10 gene and laryngeal cancer: a survival analysis. Head Neck 33, 72–76 (2011).

    PubMed  Google Scholar 

  81. Frances, C. P. et al. Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility. J. Gastroenterol. Hepatol. 22, 2298–2302 (2007).

    CAS  PubMed  Google Scholar 

  82. Fong, P. Y. et al. Association of diabetes susceptibility gene calpain-10 with pancreatic cancer among smokers. J. Gastrointest. Cancer 41, 203–208 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hill, J. W., Hu, J. J. & Evans, M. K. OGG1 is degraded by calpain following oxidative stress and cisplatin exposure. DNA Repair 7, 648–654 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhou, J., Kohl, R., Herr, B., Frank, R. & Brune, B. Calpain mediates a von Hippel-Lindau protein-independent destruction of hypoxia-inducible factor-1α. Mol. Biol. Cell 17, 1549–1558 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Huttenlocher, A., Sandborg, R. R. & Horwitz, A. F. Adhesion in cell migration. Curr. Opin. Cell Biol. 7, 697–706 (1995).

    CAS  PubMed  Google Scholar 

  86. Beckerle, M. C., Burridge, K., DeMartino, G. N. & Croall, D. E. Colocalization of calcium-dependent protease II and one of its substrates at sites of cell adhesion. Cell 51, 569–577 (1987). Interesting study that identified m-calpain localized to integrin-associated focal adhesion structures and directly cleaved the focal adhesion protein talin.

    CAS  PubMed  Google Scholar 

  87. Cuevas, B. D. et al. MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. EMBO J. 22, 3346–3355 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Huttenlocher, A. et al. Regulation of cell migration by the calcium-dependent protease calpain. J. Biol. Chem. 272, 32719–32722 (1997).

    CAS  PubMed  Google Scholar 

  89. Xu, L. & Deng, X. Suppression of cancer cell migration and invasion by protein phosphatase 2A through dephosphorylation of mu- and m-calpains. J. Biol. Chem. 281, 35567–35575 (2006).

    CAS  PubMed  Google Scholar 

  90. Postovit, L. M. et al. Calpain is required for MMP-2 and u-PA expression in SV40 large T-antigen-immortalized cells. Biochem. Biophys. Res. Commun. 297, 294–301 (2002).

    CAS  PubMed  Google Scholar 

  91. Carragher, N. O. et al. v-Src-induced modulation of the calpain-calpastatin proteolytic system regulates transformation. Mol. Cell. Biol. 22, 257–269 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Carragher, N. O., Fonseca, B. D. & Frame, M. C. Calpain activity is generally elevated during transformation but has oncogene-specific biological functions. Neoplasia 6, 53–73 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Chan, K. T., Bennin, D. A. & Huttenlocher, A. Regulation of adhesion dynamics by calpain-mediated proteolysis of focal adhesion kinase (FAK). J. Biol. Chem. 285, 11418–11426 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Franco, S. J. et al. Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nature Cell Biol. 6, 977–983 (2004).

    CAS  PubMed  Google Scholar 

  95. Yamaguchi, R., Maki, M., Hatanaka, M. & Sabe, H. Unphosphorylated and tyrosine-phosphorylated forms of a focal adhesion protein, paxillin, are substrates for calpain II in vitro: implications for the possible involvement of calpain II in mitosis-specific degradation of paxillin. FEBS Lett. 356, 114–116 (1994).

    CAS  PubMed  Google Scholar 

  96. Carragher, N. O., Levkau, B., Ross, R. & Raines, E. W. Degraded collagen fragments promote rapid disassembly of smooth muscle focal adhesions that correlates with cleavage of pp125(FAK), paxillin, and talin. J. Cell Biol. 147, 619–630 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Franco, S., Perrin, B. & Huttenlocher, A. Isoform specific function of calpain 2 in regulating membrane protrusion. Exp. Cell Res. 299, 179–187 (2004).

    CAS  PubMed  Google Scholar 

  98. Liu, X. & Schnellmann, R. G. Calpain mediates progressive plasma membrane permeability and proteolysis of cytoskeleton-associated paxillin, talin, and vinculin during renal cell death. J. Pharmacol. Exp. Ther. 304, 63–70 (2003).

    CAS  PubMed  Google Scholar 

  99. Saido, T. C. et al. Spatial resolution of fodrin proteolysis in postischemic brain. J. Biol. Chem. 268, 25239–25243 (1993).

    CAS  PubMed  Google Scholar 

  100. Sato, K. et al. Degradation of fodrin by m-calpain in fibroblasts adhering to fibrillar collagen I gel. J. Biochem. 136, 777–785 (2004).

    CAS  PubMed  Google Scholar 

  101. Wang, H. et al. PKA-mediated protein phosphorylation protects ezrin from calpain I cleavage. Biochem. Biophys. Res. Commun. 333, 496–501 (2005).

    CAS  PubMed  Google Scholar 

  102. Shuster, C. B. & Herman, I. M. Indirect association of ezrin with F-actin: isoform specificity and calcium sensitivity. J. Cell Biol. 128, 837–848 (1995).

    CAS  PubMed  Google Scholar 

  103. Yao, X., Thibodeau, A. & Forte, J. G. Ezrin-calpain I interactions in gastric parietal cells. Am. J. Physiol. 265, C36–C46 (1993).

    CAS  PubMed  Google Scholar 

  104. Serrano, K. & Devine, D. V. Vinculin is proteolyzed by calpain during platelet aggregation: 95 kDa cleavage fragment associates with the platelet cytoskeleton. Cell Motil. Cytoskeleton 58, 242–252 (2004).

    CAS  PubMed  Google Scholar 

  105. Selliah, N., Brooks, W. H. & Roszman, T. L. Proteolytic cleavage of α-actinin by calpain in T cells stimulated with anti-CD3 monoclonal antibody. J. Immunol. 156, 3215–3221 (1996).

    CAS  PubMed  Google Scholar 

  106. Raynaud, F. et al. The calpain 1-α-actinin interaction. Resting complex between the calcium-dependent protease and its target in cytoskeleton. Eur. J. Biochem. 270, 4662–4670 (2003).

    CAS  PubMed  Google Scholar 

  107. Cortesio, C. L., Boateng, L. R., Piazza, T. M., Bennin, D. A. & Huttenlocher, A. Calpain-mediated proteolysis of paxillin negatively regulates focal adhesion dynamics and cell migration. J. Biol. Chem. 286, 9998–10006 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lebart, M. C. & Benyamin, Y. Calpain involvement in the remodeling of cytoskeletal anchorage complexes. FEBS J. 273, 3415–3426 (2006).

    CAS  PubMed  Google Scholar 

  109. Glading, A., Lauffenburger, D. A. & Wells, A. Cutting to the chase: calpain proteases in cell motility. Trends Cell Biol. 12, 46–54 (2002).

    CAS  PubMed  Google Scholar 

  110. Robles, E., Huttenlocher, A. & Gomez, T. M. Filopodial calcium transients regulate growth cone motility and guidance through local activation of calpain. Neuron 38, 597–609 (2003).

    CAS  PubMed  Google Scholar 

  111. Roumes, H. et al. Calpains: markers of tumor aggressiveness? Exp. Cell Res. 316, 1587–1599 (2010).

    CAS  PubMed  Google Scholar 

  112. Perrin, B. J., Amann, K. J. & Huttenlocher, A. Proteolysis of cortactin by calpain regulates membrane protrusion during cell migration. Mol. Biol. Cell 17, 239–250 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Wolf, K. et al. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160, 267–277 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Sahai, E. & Marshall, C. J. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nature Cell Biol. 5, 711–719 (2003).

    CAS  PubMed  Google Scholar 

  115. Sanz-Moreno, V. & Marshall, C. J. The plasticity of cytoskeletal dynamics underlying neoplastic cell migration. Curr. Opin. Cell Biol. 22, 690–696 (2010).

    CAS  PubMed  Google Scholar 

  116. Wolf, K. et al. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nature Cell Biol. 9, 893–904 (2007).

    CAS  PubMed  Google Scholar 

  117. Carragher, N. O. et al. Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: a link to integrin function. Oncogene 25, 5726–5740 (2006).

    CAS  PubMed  Google Scholar 

  118. Carragher, N. O. Calpain inhibition: a therapeutic strategy targeting multiple disease states. Curr. Pharm. Des 12, 615–638 (2006).

    CAS  PubMed  Google Scholar 

  119. Cortesio, C. L. et al. Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion. J. Cell Biol. 180, 957–971 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Vosler, P. S., Brennan, C. S. & Chen, J. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol. Neurobiol. 38, 78–100 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Raynaud, F. & Marcilhac, A. Implication of calpain in neuronal apoptosis. A possible regulation of Alzheimer's disease. FEBS J. 273, 3437–3443 (2006).

    CAS  PubMed  Google Scholar 

  122. Wang, K. K. Calpain and caspase: can you tell the difference? Trends Neurosci. 23, 20–26 (2000).

    PubMed  Google Scholar 

  123. Richard, I. et al. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81, 27–40 (1995). This study identified genetic mutations in calpain 3 as a causative factor in LGMD2A.

    CAS  PubMed  Google Scholar 

  124. Tan, Y., Wu, C., De Veyra, T. & Greer, P. A. Ubiquitous calpains promote both apoptosis and survival signals in response to different cell death stimuli. J. Biol. Chem. 281, 17689–17698 (2006). An interesting study investigating the role of calpain in apoptosis and survival in response to various stimuli.

    CAS  PubMed  Google Scholar 

  125. Gonen, H., Shkedy, D., Barnoy, S., Kosower, N. S. & Ciechanover, A. On the involvement of calpains in the degradation of the tumor suppressor protein p53. FEBS Lett. 406, 17–22 (1997).

    CAS  PubMed  Google Scholar 

  126. Kubbutat, M. H. & Vousden, K. H. Proteolytic cleavage of human p53 by calpain: a potential regulator of protein stability. Mol. Cell. Biol. 17, 460–468 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Pariat, M. et al. Proteolysis by calpains: a possible contribution to degradation of p53. Mol. Cell. Biol. 17, 2806–2815 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Atencio, I. A., Ramachandra, M., Shabram, P. & Demers, G. W. Calpain inhibitor 1 activates p53-dependent apoptosis in tumor cell lines. Cell Growth Differ. 11, 247–253 (2000).

    CAS  PubMed  Google Scholar 

  129. Benetti, R. et al. The death substrate Gas2 binds m-calpain and increases susceptibility to p53-dependent apoptosis. EMBO J. 20, 2702–2714 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Sedarous, M. et al. Calpains mediate p53 activation and neuronal death evoked by DNA damage. J. Biol. Chem. 278, 26031–26038 (2003).

    CAS  PubMed  Google Scholar 

  131. Han, Y., Weinman, S., Boldogh, I., Walker, R. K. & Brasier, A. R. Tumor necrosis factor-α-inducible IκBα proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-κb activation. J. Biol. Chem. 274, 787–794 (1999).

    CAS  PubMed  Google Scholar 

  132. Pianetti, S., Arsura, M., Romieu-Mourez, R., Coffey, R. J. & Sonenshein, G. E. Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN. Oncogene 20, 1287–1299 (2001). This study implicated that calpain caused NF-κB activation, rather than IκB, following ERBB2 signalling via PI3K and AKT.

    CAS  PubMed  Google Scholar 

  133. Lee, F. Y. et al. mu-Calpain regulates receptor activator of NF-κB ligand (RANKL)-supported osteoclastogenesis via NF-κB activation in RAW 264.7 cells. J. Biol. Chem. 280, 29929–29936 (2005).

    CAS  PubMed  Google Scholar 

  134. Shumway, S. D., Maki, M. & Miyamoto, S. The PEST domain of IκBα is necessary and sufficient for in vitro degradation by mu-calpain. J. Biol. Chem. 274, 30874–30881 (1999).

    CAS  PubMed  Google Scholar 

  135. Baghdiguian, S. et al. Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IκB α/NF-κB pathway in limb-girdle muscular dystrophy type 2A. Nature Med. 5, 503–511 (1999).

    CAS  PubMed  Google Scholar 

  136. Chen, F. et al. Impairment of NF-κB activation and modulation of gene expression by calpastatin. Am. J. Physiol. Cell Physiol. 279, C709–C716 (2000).

    CAS  PubMed  Google Scholar 

  137. Small, G. W., Chou, T. Y., Dang, C. V. & Orlowski, R. Z. Evidence for involvement of calpain in c-Myc proteolysis in vivo. Arch. Biochem. Biophys. 400, 151–161 (2002).

    CAS  PubMed  Google Scholar 

  138. Conacci-Sorrell, M., Ngouenet, C. & Eisenman, R. N. Myc-nick: a cytoplasmic cleavage product of Myc that promotes α-tubulin acetylation and cell differentiation. Cell 142, 480–493 (2010). This work demonstrates that calpain can cleave the proto-oncogene Myc to Myc-nick resulting in altered cell morphology.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Niapour, M., Yu, Y. & Berger, S. A. Regulation of calpain activity by c-Myc through calpastatin and promotion of transformation in c-Myc-negative cells by calpastatin suppression. J. Biol. Chem. 283, 21371–21381 (2008).

    CAS  PubMed  Google Scholar 

  140. Wang, X. D., Rosales, J. L., Magliocco, A., Gnanakumar, R. & Lee, K. Y. Cyclin E in breast tumors is cleaved into its low molecular weight forms by calpain. Oncogene 22, 769–774 (2003).

    CAS  PubMed  Google Scholar 

  141. Schollmeyer, J. E. Calpain II involvement in mitosis. Science 240, 911–913 (1988).

    CAS  PubMed  Google Scholar 

  142. Delmas, C. et al. MAP kinase-dependent degradation of p27Kip1 by calpains in choroidal melanoma cells. Requirement of p27Kip1 nuclear export. J. Biol. Chem. 278, 12443–12451 (2003).

    CAS  PubMed  Google Scholar 

  143. Bertoli, C., Copetti, T., Lam, E. W., Demarchi, F. & Schneider, C. Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A. Oncogene 28, 721–733 (2009).

    CAS  PubMed  Google Scholar 

  144. Gafni, J., Cong, X., Chen, S. F., Gibson, B. W. & Ellerby, L. M. Calpain-1 cleaves and activates caspase-7. J. Biol. Chem. 284, 25441–25449 (2009). This study demonstrated that calpain could cleave and activate recombinant caspase 7 to produce a distinctly active form of the enzyme.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Chua, B. T., Guo, K. & Li, P. Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases. J. Biol. Chem. 275, 5131–5135 (2000).

    CAS  PubMed  Google Scholar 

  146. Tan, Y. et al. Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis. J. Biol. Chem. 281, 16016–16024 (2006).

    CAS  PubMed  Google Scholar 

  147. Martinez, J. A. et al. Calpain and caspase processing of caspase-12 contribute to the ER stress-induced cell death pathway in differentiated PC12 cells. Apoptosis 15, 1480–1493 (2010).

    CAS  PubMed  Google Scholar 

  148. Barbero, S. et al. Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis. Cancer Res. 69, 3755–3763 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Wood, D. E. et al. Bax cleavage is mediated by calpain during drug-induced apoptosis. Oncogene 17, 1069–1078 (1998).

    CAS  PubMed  Google Scholar 

  150. Gao, G. & Dou, Q. P. N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death. J. Cell. Biochem. 80, 53–72 (2000).

    CAS  PubMed  Google Scholar 

  151. Mandic, A. et al. Calpain-mediated Bid cleavage and calpain-independent Bak modulation: two separate pathways in cisplatin-induced apoptosis. Mol. Cell. Biol. 22, 3003–3013 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Gil-Parrado, S. et al. Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members. J. Biol. Chem. 277, 27217–27226 (2002).

    CAS  PubMed  Google Scholar 

  153. Li, B. & Dou, Q. P. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc. Natl Acad. Sci. USA 97, 3850–3855 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Toyota, H. et al. Calpain-induced Bax-cleavage product is a more potent inducer of apoptotic cell death than wild-type Bax. Cancer Lett. 189, 221–230 (2003).

    CAS  PubMed  Google Scholar 

  155. Lin, L., Ye, Y. & Zakeri, Z. p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death. Cell Death Differ. 13, 141–150 (2006).

    PubMed  Google Scholar 

  156. Fettucciari, K. et al. Group B Streptococcus induces macrophage apoptosis by calpain activation. J. Immunol. 176, 7542–7556 (2006).

    CAS  PubMed  Google Scholar 

  157. Hirai, S., Kawasaki, H., Yaniv, M. & Suzuki, K. Degradation of transcription factors, c-Jun and c-Fos, by calpain. FEBS Lett. 287, 57–61 (1991).

    CAS  PubMed  Google Scholar 

  158. Pariat, M. et al. The sensitivity of c-Jun and c-Fos proteins to calpains depends on conformational determinants of the monomers and not on formation of dimers. Biochem. J. 345, 129–138 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Kim, M. J. et al. Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death. Proc. Natl Acad. Sci. USA 99, 9870–9875 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Porn-Ares, M. I., Samali, A. & Orrenius, S. Cleavage of the calpain inhibitor, calpastatin, during apoptosis. Cell Death Differ. 5, 1028–1033 (1998).

    CAS  PubMed  Google Scholar 

  161. Wang, K. K. et al. Caspase-mediated fragmentation of calpain inhibitor protein calpastatin during apoptosis. Arch. Biochem. Biophys. 356, 187–196 (1998).

    CAS  PubMed  Google Scholar 

  162. Takano, J. et al. Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice. J. Biol. Chem. 280, 16175–16184 (2005).

    CAS  PubMed  Google Scholar 

  163. Polster, B. M., Basanez, G., Etxebarria, A., Hardwick, J. M. & Nicholls, D. G. Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria. J. Biol. Chem. 280, 6447–6454 (2005).

    CAS  PubMed  Google Scholar 

  164. Liu, L., Xing, D. & Chen, W. R. Micro-calpain regulates caspase-dependent and apoptosis inducing factor-mediated caspase-independent apoptotic pathways in cisplatin-induced apoptosis. Int. J. Cancer 125, 2757–2766 (2009).

    CAS  PubMed  Google Scholar 

  165. Vosler, P. S. et al. Calcium dysregulation induces apoptosis-inducing factor release: cross-talk between PARP-1- and calpain-signaling pathways. Exp. Neurol. 218, 213–220 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nature Rev. Cancer 7, 961–967 (2007).

    CAS  Google Scholar 

  167. Ravikumar, B. et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90, 1383–1435 (2010).

    CAS  PubMed  Google Scholar 

  168. Yousefi, S. et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nature Cell Biol. 8, 1124–1132 (2006). This study was one of the first to assess the contribution of calpain to autophagy, showing that calpain-mediated cleavage of ATG5 provoked apoptotic cell death.

    CAS  PubMed  Google Scholar 

  169. Williams, A. et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature Chem. Biol. 4, 295–305 (2008).

    CAS  Google Scholar 

  170. Demarchi, F. et al. Calpain is required for macroautophagy in mammalian cells. J. Cell Biol. 175, 595–605 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Cheng, Y. et al. Apoptosis-suppressing and autophagy-promoting effects of calpain on oridonin-induced L929 cell death. Arch. Biochem. Biophys. 475, 148–155 (2008).

    CAS  PubMed  Google Scholar 

  172. Demarchi, F., Bertoli, C., Greer, P. A. & Schneider, C. Ceramide triggers an NF-κB-dependent survival pathway through calpain. Cell Death Differ. 12, 512–522 (2005).

    CAS  PubMed  Google Scholar 

  173. Li, C. et al. Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IκBα degradation. J. Biol. Chem. 285, 16096–16104 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Liu, T. L. et al. Enhancement of chemosensitivity toward peplomycin by calpastatin-stabilized NF-κB p65 in esophageal carcinoma cells: possible involvement of Fas/Fas-L synergism. Apoptosis 11, 1025–1037 (2006).

    CAS  PubMed  Google Scholar 

  175. Mlynarczuk-Bialy, I. et al. Combined effect of proteasome and calpain inhibition on cisplatin-resistant human melanoma cells. Cancer Res. 66, 7598–7605 (2006).

    CAS  PubMed  Google Scholar 

  176. Kulkarni, S. et al. Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer. Oncogene 29, 1339–1350 (2010).

    CAS  PubMed  Google Scholar 

  177. Pelley, R. P. et al. Calmodulin-androgen receptor (AR) interaction: calcium-dependent, calpain-mediated breakdown of AR in LNCaP prostate cancer cells. Cancer Res. 66, 11754–11762 (2006).

    CAS  PubMed  Google Scholar 

  178. Chen, H. et al. ERK regulates calpain 2-induced androgen receptor proteolysis in CWR22 relapsed prostate tumor cell lines. J. Biol. Chem. 285, 2368–2374 (2010).

    CAS  PubMed  Google Scholar 

  179. Libertini, S. J. et al. Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. Cancer Res. 67, 9001–9005 (2007).

    CAS  PubMed  Google Scholar 

  180. Storr, S. J. et al. Calpain-1 expression is associated with relapse-free survival in breast cancer patients treated with trastuzumab following adjuvant chemotherapy. Int. J. Cancer 8 Mar 2011 (doi:10.1002/ijc.25832).

    CAS  PubMed  Google Scholar 

  181. Del Bello, B., Moretti, D., Gamberucci, A. & Maellaro, E. Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status. Oncogene 26, 2717–2726 (2007).

    CAS  PubMed  Google Scholar 

  182. Liu, L. et al. Calpain-mediated pathway dominates cisplatin-induced apoptosis in human lung adenocarcinoma cells as determined by real-time single cell analysis. Int. J. Cancer 122, 2210–2222 (2008).

    CAS  PubMed  Google Scholar 

  183. Donkor, I. O. A survey of calpain inhibitors. Curr. Med. Chem. 7, 1171–1188 (2000).

    CAS  PubMed  Google Scholar 

  184. Todd, B. et al. A structural model for the inhibition of calpain by calpastatin: crystal structures of the native domain VI of calpain and its complexes with calpastatin peptide and a small molecule inhibitor. J. Mol. Biol. 328, 131–146 (2003).

    CAS  PubMed  Google Scholar 

  185. Wang, K. K. et al. An α-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective. Proc. Natl Acad. Sci. USA 93, 6687–6692 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Graybill, T. L. et al. Inhibition of human erythrocyte calpain-I by novel quinoline carboxamides. Bioorg. Med. Chem. Lett. 5, 387–392 (1995).

    CAS  Google Scholar 

  187. Zatz, M. & Starling, A. Calpains and disease. N. Engl. J. Med. 352, 2413–2423 (2005).

    CAS  PubMed  Google Scholar 

  188. Biswas, S., Harris, F., Dennison, S., Singh, J. & Phoenix, D. A. Calpains: targets of cataract prevention? Trends Mol. Med. 10, 78–84 (2004).

    CAS  PubMed  Google Scholar 

  189. Shields, D. C., Schaecher, K. E., Saido, T. C. & Banik, N. L. A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. Proc. Natl Acad. Sci. USA 96, 11486–11491 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Mani, S. K. et al. Calpain inhibition preserves myocardial structure and function following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 297, H1744–H1751 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Horikawa, Y. et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet. 26, 163–175 (2000).

    CAS  PubMed  Google Scholar 

  192. Saez, M. E. et al. Calpain-5 gene variants are associated with diastolic blood pressure and cholesterol levels. BMC Med. Genet. 8, 1 (2007).

    PubMed  PubMed Central  Google Scholar 

  193. Gonzalez, A. et al. Specific haplotypes of the CALPAIN-5 gene are associated with polycystic ovary syndrome. Hum. Reprod. 21, 943–951 (2006).

    CAS  PubMed  Google Scholar 

  194. Penna, I., Du, H., Ferriani, R. & Taylor, H. S. Calpain5 expression is decreased in endometriosis and regulated by HOXA10 in human endometrial cells. Mol. Hum. Reprod. 14, 613–618 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Kerbiriou, M., Teng, L., Benz, N., Trouve, P. & Ferec, C. The calpain, caspase 12, caspase 3 cascade leading to apoptosis is altered in F508del-CFTR expressing cells. PLoS ONE 4, e8436 (2009).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the laboratory of S.G.M. is funded by Cancer Research UK (CRUK) and the Breast Cancer Campaign, UK. Work in the laboratory of M.C.F. is funded by Cancer Research UK. N.O.C. is supported by a CRUK fellowship award. Work in the laboratory of T.P. is funded by Biotechnology and Biological Sciences Research Council (BBSRC), UK. The authors thank C. Woolston for critical review of the manuscript.

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Glossary

C2 domain

A structural domain that is involved in membrane targeting. The C2-like domain of calpain has superficial similarity to the C2 domain of other enzymes.

EF hand

A structural domain responsible for calcium binding, found in calcium-binding proteins.

L domain

Contains the XL region and is found at the N-terminal of calpastatin. Not much is known about the functions of this domain; however, many splicing events occur in this region.

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Storr, S., Carragher, N., Frame, M. et al. The calpain system and cancer. Nat Rev Cancer 11, 364–374 (2011). https://doi.org/10.1038/nrc3050

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