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Hiroyuki Sorimachi - One of the best experts on this subject based on the ideXlab platform.
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Calpain research for drug discovery challenges and potential
Nature Reviews Drug Discovery, 2016Co-Authors: Yasuko Ono, Takaomi C. Saido, Hiroyuki SorimachiAbstract:Calpains are a family of proteases that were scientifically recognized earlier than proteasomes and caspases, but remain enigmatic. However, they are known to participate in a multitude of physiological and pathological processes, performing 'limited proteolysis' whereby they do not destroy but rather modulate the functions of their substrates. Calpains are therefore referred to as 'modulator proteases'. Multidisciplinary research on Calpains has begun to elucidate their involvement in pathophysiological mechanisms. Therapeutic strategies targeting malfunctions of Calpains have been developed, driven primarily by improvements in the specificity and bioavailability of Calpain inhibitors. Here, we review the Calpain superfamily and Calpain-related disorders, and discuss emerging Calpain-targeted therapeutic strategies.
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Calpains in Health and Disease
Proteases: Structure and Function, 2013Co-Authors: John Anagli, Kevin K.w. Wang, Yasuko Ono, Hiroyuki SorimachiAbstract:Since the first report in 1964 (Guroff 1964) of a cytosolic Ca2+-dependent neutral proteolytic activity, now known as Calpain-1 (also called μ-Calpain), other members of the Calpain family of proteinases have been discovered (Croall and DeMartino 1991; Molinari and Carafoli 1997; Goll et al. 2003; Bertipaglia and Carafoli 2007; Croall and Ersfeld 2007; Sorimachi et al. 2010, 2011a). The Calpains are defined as having amino acid (aa) sequences significantly similar to that of the protease domain of human Calpain-1. Calpains also contain a variety of protein structural motifs including C2, Calpain-type β-sandwich (CBSW), Zn-finger and penta-EF-hand (PEF) domains. This important class of intracellular cysteine proteases is found in almost all eukaryotes and some bacteria. To date, 15 Calpain genes have been identified in humans (see Fig. 12.1). However, mammalian Calpain-1 and -2, sometimes referred to as the “ubiquitous,” “conventional,” or “classical” Calpains, are the best-characterized members of the Calpain superfamily (Clan CA, family C02, EC 3.4.22.17). The conventional Calpains have a very specific proteinaceous inhibitor in vivo called calpastatin. The ubiquitous Calpain-1 and -2 and their natural inhibitor calpastatin are the three members of the Calpain system that have been studied most extensively at the structure-functional level. Under normal physiological conditions, Calpains exist at very low activity in cells and are proposed to participate in important cellular activities, including signal transduction, cell motility and apoptosis. However, excessive Calpain activation following ischemic and traumatic cell injury or aberrant expression of components of the Calpain system results in cell death or impaired cellular function. This review summarizes current knowledge of the biological significance of regulated Calpain activity and the pathological consequences of uncontrolled or excessive Calpain activation, with special emphasis on the pathophysiological roles of the Calpains in ischemic and traumatic brain injury and some tissue-specific diseases.
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Calpains: an elaborate proteolytic system.
Biochimica et biophysica acta, 2011Co-Authors: Yasuko Ono, Hiroyuki SorimachiAbstract:Calpain is an intracellular Ca(2+)-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02). Recent expansion of sequence data across the species definitively shows that Calpain has been present throughout evolution; Calpains are found in almost all eukaryotes and some bacteria, but not in archaebacteria. Fifteen genes within the human genome encode a Calpain-like protease domain. Interestingly, some human Calpains, particularly those with non-classical domain structures, are very similar to Calpain homologs identified in evolutionarily distant organisms. Three-dimensional structural analyses have helped to identify Calpain's unique mechanism of activation; the Calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to Ca(2+)via well-conserved amino acids. This finding highlights the mechanistic characteristics shared by the numerous Calpain homologs, despite the fact that they have divergent domain structures. In other words, Calpains function through the same mechanism but are regulated independently. This article reviews the recent progress in Calpain research, focusing on those studies that have helped to elucidate its mechanism of action. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
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Calpain 8/nCL-2 and Calpain 9/nCL-4 Constitute an Active Protease Complex, G-Calpain, Involved in Gastric Mucosal Defense
PLoS genetics, 2010Co-Authors: Shoji Hata, Manabu Abe, Hidenori Suzuki, Fujiko Kitamura, Noriko Toyama-sorimachi, Keiko Abe, Kenji Sakimura, Hiroyuki SorimachiAbstract:Calpains constitute a superfamily of Ca2+-dependent cysteine proteases, indispensable for various cellular processes. Among the 15 mammalian Calpains, Calpain 8/nCL-2 and Calpain 9/nCL-4 are predominantly expressed in the gastrointestinal tract and are restricted to the gastric surface mucus (pit) cells in the stomach. Possible functions reported for Calpain 8 are in vesicle trafficking between ER and Golgi, and Calpain 9 are implicated in suppressing tumorigenesis. These highlight that Calpains 8 and 9 are regulated differently from each other and from conventional Calpains and, thus, have potentially important, specific functions in the gastrointestinal tract. However, there is no direct evidence implicating Calpain 8 or 9 in human disease, and their properties and physiological functions are currently unknown. To address their physiological roles, we analyzed mice with mutations in the genes for these Calpains, Capn8 and Capn9. Capn8−/− and Capn9−/− mice were fertile, and their gastric mucosae appeared normal. However, both mice were susceptible to gastric mucosal injury induced by ethanol administration. Moreover, the Capn8−/− stomach showed significant decreases in both Calpains 9 and 8, and the same was true for Capn9−/−. Consistent with this finding, in the wild-type stomach, Calpains 8 and 9 formed a complex we termed “G-Calpain,” in which both were essential for activity. This is the first example of a “hybrid” Calpain complex. To address the physiological relevance of the Calpain 8 proteolytic activity, we generated Calpain 8:C105S “knock-in” (Capn8CS/CS) mice, which expressed a proteolytically inactive, but structurally intact, Calpain 8. Although, unlike the Capn8−/− stomach, that of the Capn8CS/CS mice expressed a stable and active Calpain 9, the mice were susceptible to ethanol-induced gastric injury. These results provide the first evidence that both of the gastrointestinal-tract-specific Calpains are essential for gastric mucosal defense, and they point to G-Calpain as a potential target for gastropathies caused by external stresses.
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New era of Calpain research. Discovery of tissue-specific Calpains.
FEBS letters, 1994Co-Authors: Hiroyuki Sorimachi, Takaomi C. Saido, Koichi SuzukiAbstract:The recent discovery of several new Calpain species other than the two species thus far studied reveals that Calpain, especially the Calpain large subunit, constitutes a family comprising at least six members that can be classified into ubiquitous (mu, m- and mu/m-types) and tissue-specific (p94 or nCL-1 specific for skeletal muscle, and nCL-2 and -2' specific for stomach) Calpains. The newly identified tissue-specific Calpains have various characteristics distinct from conventional Calpains in structure, manner of expression, and enzyme activity. Unique features of tissue specific Calpains are discussed together with the evolutionary view of the Calpain large subunit.
Zhen-shun Cheng - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the erk1 2 ubiquitous Calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro
Experimental Cell Research, 2020Co-Authors: Menglin Zou, Guqin Zhang, Jingfeng Zou, Yuan Liu, Bing Liu, Zhen-shun ChengAbstract:Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in IPF. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) cascade, which regulates EMT and oncogenesis, has been implicated in the pathogenesis of IPF. Calpains, Ca2+-dependent cysteine proteinases that mediate controlled proteolysis of many specific substrates including epithelial cell marker E-cadherin, participate in organ fibrosis. Calpain-1 and Calpain-2 of Calpain family are ubiquitous Calpains. ERK1/2 signaling stimulates the ubiquitous Calpains activity in cancer development, but whether ERK1/2 signaling mediates the ubiquitous Calpains activity in pulmonary fibrosis is unknown. Here we investigated whether inhibition of ERK1/2 signaling and the ubiquitous Calpains attenuated experimental pulmonary fibrosis and examined the potential mechanism. Our results showed that inhibition of ERK1/2 signaling and the ubiquitous Calpains both attenuated bleomycin (BLM)-induced lung fibrosis in mice. Inhibition of ERK1/2 signaling downregulated the expression of Calpain-1 and Calpain-2 in vivo and in vitro. We detected decreased E-cadherin expression and increased Calpain-1 expression in IPF patients. Inhibition of ERK1/2 signaling and the ubiquitous Calpains both suppressed the development of EMT in vivo and in vitro. Our study indicated that inhibition of the ERK1/2-ubiquitous Calpains pathway protected pulmonary fibrosis from BLM, possibly via inhibition of EMT. Therefore, targeting ubiquitous Calpains may be a potential strategy to attenuate IPF.
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Inhibition of the ERK1/2-ubiquitous Calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro.
Experimental cell research, 2020Co-Authors: Menglin Zou, Guqin Zhang, Jingfeng Zou, Yuan Liu, Bing Liu, Zhen-shun ChengAbstract:Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in IPF. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) cascade, which regulates EMT and oncogenesis, has been implicated in the pathogenesis of IPF. Calpains, Ca2+-dependent cysteine proteinases that mediate controlled proteolysis of many specific substrates including epithelial cell marker E-cadherin, participate in organ fibrosis. Calpain-1 and Calpain-2 of Calpain family are ubiquitous Calpains. ERK1/2 signaling stimulates the ubiquitous Calpains activity in cancer development, but whether ERK1/2 signaling mediates the ubiquitous Calpains activity in pulmonary fibrosis is unknown. Here we investigated whether inhibition of ERK1/2 signaling and the ubiquitous Calpains attenuated experimental pulmonary fibrosis and examined the potential mechanism. Our results showed that inhibition of ERK1/2 signaling and the ubiquitous Calpains both attenuated bleomycin (BLM)-induced lung fibrosis in mice. Inhibition of ERK1/2 signaling downregulated the expression of Calpain-1 and Calpain-2 in vivo and in vitro. We detected decreased E-cadherin expression and increased Calpain-1 expression in IPF patients. Inhibition of ERK1/2 signaling and the ubiquitous Calpains both suppressed the development of EMT in vivo and in vitro. Our study indicated that inhibition of the ERK1/2-ubiquitous Calpains pathway protected pulmonary fibrosis from BLM, possibly via inhibition of EMT. Therefore, targeting ubiquitous Calpains may be a potential strategy to attenuate IPF.
Koichi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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New era of Calpain research. Discovery of tissue-specific Calpains.
FEBS letters, 1994Co-Authors: Hiroyuki Sorimachi, Takaomi C. Saido, Koichi SuzukiAbstract:The recent discovery of several new Calpain species other than the two species thus far studied reveals that Calpain, especially the Calpain large subunit, constitutes a family comprising at least six members that can be classified into ubiquitous (mu, m- and mu/m-types) and tissue-specific (p94 or nCL-1 specific for skeletal muscle, and nCL-2 and -2' specific for stomach) Calpains. The newly identified tissue-specific Calpains have various characteristics distinct from conventional Calpains in structure, manner of expression, and enzyme activity. Unique features of tissue specific Calpains are discussed together with the evolutionary view of the Calpain large subunit.
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Sequence comparison among muscle-specific Calpain, p94, and Calpain subunits.
Biochimica et biophysica acta, 1992Co-Authors: Hiroyuki Sorimachi, Koichi SuzukiAbstract:Abstract While conventional Calpains, m- and μ-Calpains named accoding to their calcium-dependence, are expressed in almost every tissues, mRNA of newly identified p94, which has a significant sequence similarity to the conventional Calpain large subunits, is abundantly expressed only in skeletal muscle. In addition to this specific expression, p94 is distinct from conventional Calpains in that it contains three unique regions showing no similarity to conventional Calpain subunits. When rat and human p94 are compared, overall sequence similarity is 94.0%, which is close to those for m- and μ-Calpain large subunits; 93.1% and 95.4% between human and rabbit, respectively, suggesting the evolutionary importance of p94. These Calpain large subunit proteins, p94, m- and μ-types, can be considered to constitute a super family, whose p94, m- and μ-types reresent the three major types. Sequences of the Calpain large-subunit family members, including the recently reported Schistosoma Calpain, are compared. Their evolutionary correlation and function are discussed on the basis of the results thus far obtained.
Menglin Zou - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the erk1 2 ubiquitous Calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro
Experimental Cell Research, 2020Co-Authors: Menglin Zou, Guqin Zhang, Jingfeng Zou, Yuan Liu, Bing Liu, Zhen-shun ChengAbstract:Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in IPF. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) cascade, which regulates EMT and oncogenesis, has been implicated in the pathogenesis of IPF. Calpains, Ca2+-dependent cysteine proteinases that mediate controlled proteolysis of many specific substrates including epithelial cell marker E-cadherin, participate in organ fibrosis. Calpain-1 and Calpain-2 of Calpain family are ubiquitous Calpains. ERK1/2 signaling stimulates the ubiquitous Calpains activity in cancer development, but whether ERK1/2 signaling mediates the ubiquitous Calpains activity in pulmonary fibrosis is unknown. Here we investigated whether inhibition of ERK1/2 signaling and the ubiquitous Calpains attenuated experimental pulmonary fibrosis and examined the potential mechanism. Our results showed that inhibition of ERK1/2 signaling and the ubiquitous Calpains both attenuated bleomycin (BLM)-induced lung fibrosis in mice. Inhibition of ERK1/2 signaling downregulated the expression of Calpain-1 and Calpain-2 in vivo and in vitro. We detected decreased E-cadherin expression and increased Calpain-1 expression in IPF patients. Inhibition of ERK1/2 signaling and the ubiquitous Calpains both suppressed the development of EMT in vivo and in vitro. Our study indicated that inhibition of the ERK1/2-ubiquitous Calpains pathway protected pulmonary fibrosis from BLM, possibly via inhibition of EMT. Therefore, targeting ubiquitous Calpains may be a potential strategy to attenuate IPF.
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Inhibition of the ERK1/2-ubiquitous Calpains pathway attenuates experimental pulmonary fibrosis in vivo and in vitro.
Experimental cell research, 2020Co-Authors: Menglin Zou, Guqin Zhang, Jingfeng Zou, Yuan Liu, Bing Liu, Zhen-shun ChengAbstract:Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease with poor prognosis. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in IPF. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) cascade, which regulates EMT and oncogenesis, has been implicated in the pathogenesis of IPF. Calpains, Ca2+-dependent cysteine proteinases that mediate controlled proteolysis of many specific substrates including epithelial cell marker E-cadherin, participate in organ fibrosis. Calpain-1 and Calpain-2 of Calpain family are ubiquitous Calpains. ERK1/2 signaling stimulates the ubiquitous Calpains activity in cancer development, but whether ERK1/2 signaling mediates the ubiquitous Calpains activity in pulmonary fibrosis is unknown. Here we investigated whether inhibition of ERK1/2 signaling and the ubiquitous Calpains attenuated experimental pulmonary fibrosis and examined the potential mechanism. Our results showed that inhibition of ERK1/2 signaling and the ubiquitous Calpains both attenuated bleomycin (BLM)-induced lung fibrosis in mice. Inhibition of ERK1/2 signaling downregulated the expression of Calpain-1 and Calpain-2 in vivo and in vitro. We detected decreased E-cadherin expression and increased Calpain-1 expression in IPF patients. Inhibition of ERK1/2 signaling and the ubiquitous Calpains both suppressed the development of EMT in vivo and in vitro. Our study indicated that inhibition of the ERK1/2-ubiquitous Calpains pathway protected pulmonary fibrosis from BLM, possibly via inhibition of EMT. Therefore, targeting ubiquitous Calpains may be a potential strategy to attenuate IPF.
Katsuji Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Abundance of Calpain and aggrecan-cleavage products of Calpain in degenerated human intervertebral discs.
Osteoarthritis and cartilage, 2011Co-Authors: S. Fukuta, K Suzuki, Kei Miyamoto, H. Maehara, T. Inoue, K. Kikuike, Katsuji ShimizuAbstract:Summary Objective To assess the expression of Calpains and Calpain-induced aggrecan fragmentation in early and advanced stages of degeneration of human intervertebral discs (IVDs). Design Disc tissue samples of 55 patients (mean age, 51.2 ± 22.3 years) who underwent intervertebral fusion were divided into groups with early and advanced degeneration based on the Thompson magnetic resonance imaging (MRI) scale. In advanced degeneration group, five patients (mean age, 35.5 ± 11.4 years) of lumbar disc herniation (LDH) were included. Protein levels of m- and μ-Calpains and their inhibitor calpastatin were assayed, and immunohistochemical techniques were used to localize and quantify the production of the enzymes. To investigate Calpain activity, we assayed purified aggrecan fragmentation in disc tissue by Western blotting and immunohistochemistry with VPGVA antibody, which recognizes the m-Calpain generated neo-epitope GVA. Results Discs at early stages of degeneration expressed low levels of m- and μ-Calpains and calpastatin, and few cells expressed degenerative enzymes. At more advanced stages of degeneration, the expression and number of cells immunopositive for m-Calpain, μ-Calpain and calpastatin were significantly higher. Further finding showed that anti-GVA-reactive aggrecan fragments were significantly higher in discs at advanced compared with early stages of degeneration. Herniated disc samples showed stronger expression and more cells immunopositive for Calpains, calpastatin and GVA in the nucleus pulposus than in the annulus fibrous. Conclusions The expression of Calpains, together with m-Calpain-induced degradation products of extracellular matrix, was correlated with the degree of disc degeneration in human IVD tissue. These findings suggest that Calpains may be involved in IVD degeneration via proteoglycan (PG) cleavage.
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Calcium-dependent cysteine proteinase (Calpain) in human arthritic synovial joints.
Arthritis & Rheumatism, 1992Co-Authors: Shingo Yamamoto, Yasuaki Nakagawa, Katsuji Shimizu, Kiichi Suzuki, Takao YamamuroAbstract:Objective. To study the roles of Calpains in the synovial joint in rheumatoid arthritis (RA) and osteoarthritis (OA) and to verify the hypothesis that Calpains present in the synovial fluid come from the synovium. Methods. We performed immunohistochemical, biochemical, and immunoblotting analyses for Calpains in synovial tissues, synovial cell cultures, and synovial fluids. Results. Immunohistochemical staining of RA synovium demonstrated specific cytoplasmic staining of cells in the synovial lining layer, storomal fibroblasts, and endothelial cells. OA synovium showed almost the same intensity and distribution of Calpain staining. DEAE-cellulose chromatography of RA and OA synovial extracts and synovial fluids showed a peak of caseinolytic activity attributable to Calpain, as well as an inhibitory peak of calpastatin, a specific inhibitor protein of Calpains. Immunoblotting using the antiCalpain antibody from the Calpain peak of RA and OA synovium and synovial fluid showed identity with the heavy subunit of Calpain (80 kd). Similarly, Calpain existed in the same form (80 kd) in conditioned media (supernatant) obtained from synovial cell cultures, as well as in the synoviocytes. The total specific activity of the 2 Calpains in the synovial fluid of RA patients was higher than that of calpastatin. Conclusion. The findings suggest that the extracellular appearance of Calpains could be due to the secretion of these proteins from the synovial cells and that Calpains may play a role in cartilage damage of RA and OA that occurs in synovial joints.
