Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.54 (calpain 3)
 430 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine phosphorylation of cellular proteins is an early and key step after activation of the insulin receptor kinase (IRK). The study of the properties of these proteins should contribute to our understanding of insulin action. In rat hepatoma cells overexpressing human insulin receptors (HTC-IR), insulin treatment resulted in rapid tyrosine phosphorylation of proteins of 180, 94, 68, and 60 kDa. When lysates from insulin-treated cells were immunoprecipitated with anti-Syp antibody, subsequent immunoblotting identified p65 and p68, which reacted with anti-Syp, and p6O and p68, which reacted with antiphosphotyrosine antibody. Thus, insulin treatment yielded tyrosine phosphorylation of both Syp and a Syp-associated p6O molecule. When lysates from insulin-treated cells were adsorbed with a glutathione S-transferase (GST)-Syp-Src homology-2 (SH2) fusion protein, tyrosine- phosphorylated p6O was sequestered. After subjecting lysates to SDS-PAGE, the GST-SypSH2 fusion protein was found to bind to p18O, p94, and p6O. Thus, Syp associates directly with a 60-kDa IRK substrate via its SH2 domains. Syp-associated p6O differed from the 60- to 62-kDa proteins, associating with ras guanosine triphosphatase-activating protein, which also underwent modest tyrosine phosphorylation in response to insulin. Preadsorption of cell lystates with antibody against the 85-kDa subunit (p85) of phosphatidylinositol 3-kinase substantially reduced the amount of p60 subsequently immunoprecipitated by anti-Syp. Thus, p60 associates with both Syp and p85. The amount of tyrosine-phosphorylated p60 exceeded that of p180 in anti-Syp immunoprecipitates, whereas their proportion was comparable in anti-p85 immunoprecipitates. Grb2 was also observed in the anti-Syp immunoprecipitates. When lysates from insulin-treated cells were adsorbed with GST-p85SH2 domains or GST-Grb2, the subsequent eluates contained tyrosine-phosphorylated p60, as determined by immunoblotting with antiphosphotyrosine. Membrane binding assays using GST fusion proteins showed that these associations were direct. Studies in rat liver, muscle, and adipose tissue identified insulin-dependent association of Syp, Grb2, and p85 with tyrosine-phosphorylated p60 in adipose tissue only. We conclude that insulin treatment of HTC-IR cells and rat adipose tissue results in the tyrosine phosphorylation of p60, which might participate in the recruitment of downstream effectors involved in insulin signal transduction.
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PMID:A 60-kilodalton protein in rat hepatoma cells overexpressing insulin receptor was tyrosine phosphorylated and associated with Syp, phophatidylinositol 3-kinase, and Grb2 in an insulin-dependent manner. 877 Aug 81

A branch of a highly inbred family was referred for prenatal counseling with an initial misdiagnosis of Becker Muscular Dystrophy (BMD) due to the limited clinical and laboratory data obtained in pre-dystrophin era and hidden family information. In a second branch of the family with a diagnosis of limb-girdle muscular dystrophy type 2A (LGMD2A) molecular studies revealed a homozygous 550 delta A mutation in the calcium-activated neutral protease 3 (calpain 3, CANP3) gene in the affected members. Finally, in the third branch of the family, it turned out that both parents were heterozygous for the 550 delta A mutation and the 13-week-old fetus was homozygous. The same mutation subsequently also was found in the first branch of the family. The parents were informed that the risk of their child of developing the disease would be very high given that he was carrying the same homozygous mutation of the other affected members. They were informed also that in another population (in Reunion Island) the same disease does not necessarily follow such a simple pattern of inheritance. After counseling the parents decided to terminate the pregnancy.
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PMID:Prenatal diagnosis of limb-girdle muscular dystrophy type 2A. 878 5

The Caenorhabditis elegans sex determination gene tra-3 is required for the correct sexual development of the soma and germ line in hermaphrodites, while being fully dispensable in males. Genetic analysis of tra-3 has suggested that its product may act as a potentiator of another sex determination gene, tra-2. Molecular analysis reported here reveals that the predicted tra-3 gene product is a member of the calpain family of calcium-regulated cytosolic proteases, though it lacks the calcium binding regulatory domain. Calpains are regulatory processing proteases, exhibiting marked substrate specificity, and mutations in the p94 isoform underlie the human hereditary condition limb-girdle muscular dystrophy type 2A. The molecular identity of TRA-3 is consistent with previous genetic analysis which suggested that tra-3 plays a very selective modulatory role and is required in very small amounts. Based on these observations and new genetic data, we suggest a refinement of the position of tra-3 within the sex determination cascade and discuss possible mechanisms of action for the TRA-3 protein.
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PMID:The tra-3 sex determination gene of Caenorhabditis elegans encodes a member of the calpain regulatory protease family. 888 39

A reclassification of the limb-girdle types of autosomal recessive muscular dystrophy based on genetic and protein information has been made possible by major advances over the past 2 years. At least six different forms of limb-girdle types of autosomal recessive muscular dystrophy can be defined by their genetic basis, with at least two pathogenic mechanisms involved. Three forms are defined by involvement of different proteins of the sarcoglycan complex, while a muscle specific protease (calpain 3) is implicated in another form of the recessive disease. These findings provide the basis for a new diagnostic approach to the group, with molecular techniques now an essential part of the diagnostic process. A scheme for diagnosis in this group is proposed.
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PMID:Advances in the molecular genetics of the limb-girdle type of autosomal recessive progressive muscular dystrophy. 901 5

The expression and the putative function(s) of a specific muscle calcium-dependent protease were investigated during myogenesis using rat myoblast primary cultures as a model. We have shown that the levels of p94 mRNAs increase as a function of myoblast differentiation, with the greatest amount of these RNAs being present during the later stages (8th day after plating). After an antisense oligodeoxyribonucleotide treatment with p94, ultrastructural studies show dramatic perturbations in differentiated myotubes and during myofibrillogenesis, mainly involving myofibrillar stability and Z-line integrity. These results may be related to recent findings about the role of p94 gene mutations in limbgirdle muscular dystrophy type 2A.
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PMID:Evidence for implication of muscle-specific calpain (p94) in myofibrillar integrity. 893 Mar 95

The Syrian cardiomyopathic hamster (BIO14.6), that develops both muscular dystrophy and progressive cardiomyopathy, is widely used as an animal model of autosomal recessive cardiomyopathy mimicking human hypertrophic cardiomyopathy, and five genes have been proposed as strong candidates for the cause of cardiomyopathy. We recently mapped the cardiomyopathy locus of the hamster to the centromeric region of chromosome 9qa2.1-b1 by construction of a genetic linkage map of the Syrian hamster. Thus, we analyzed the loci of the five candidate genes, alpha tropomyosin, cardiac troponin T, adhalin, calpain 3 and cardiac myosin binding protein-C, by the FISH method, and found that these genes were mapped on the distal portion of chromosome 12qa5 and 4pa2 and the proximal portion of chromosomes 9qb7, 1qc1.1 and 1qb3, respectively. These results provide strong evidence that the five candidate genes previously proposed are not related to the hamster cardiomyopathy.
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PMID:Five candidate genes for hamster cardiomyopathy did not map to the cardiomyopathy locus by FISH analysis. 894 68

p94 belongs to the calcium-dependent cysteine protease (calpain) family which has been detected from human to mold. In contrast to the conventional m- and mu-calpains which are expressed ubiquitously, expression of p94 predominates in skeletal muscle, and the mRNA for p94 is at least 10-times more abundant than mRNAs encoding in the m- and mu-types. The unique feature of p94 is that it undergoes rapid and exhaustive autolysis with a half-life of less than half an hour. To elucidate the nature of specific and abundant expression in skeletal muscle, and to proceed toward gene targeting p94, we have cloned and characterized mouse and rat genes for p94, and compared them with that of the human sequence. The sequence comparison among three mammalian species revealed several conserved regions including possible transcription factor binding sites. Furthermore, mouse and rat upstream regions of p94 are conserved over 3 kb suggesting that expression of p94 in skeletal muscle of both rodents is similarly regulated.
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PMID:Highly conserved structure in the promoter region of the gene for muscle-specific calpain, p94. 899 99

Lobster skeletal muscles contain four Ca2+-dependent cysteine proteinases (CDPs I, IIa, IIb, and III) that degrade myofibrillar proteins. Lobster CDPs share many properties with calpains from vertebrate tissues, but differ in native mass and subunit composition. Recently, cDNAs encoding a calpain-like protein (Dm-calpain; 91.5 or 94 kDa) have been isolated from fruit fly, Drosophila melanogaster. To further clarify the relationship between invertebrate CDPs and mammalian calpains, antibodies specific for mu-, m-, p94 (nCL-1), and Dm-calpains and lobster CDP IIb (native M(r) 195,000, subunit M(r) 95,000) were used in immunoblots to test for antigenic cross-reactivity. No common epitopes were found between CDP IIb and vertebrate calpains. However, polyclonal antibodies to CDP IIb cross-reacted strongly with a C-terminal 70-kDa portion of Dm-calpain expressed in Escherichia coli. Conversely, polyclonal antibodies to Dm-calpain recognized CDP IIb. A second CDP, CDP IIa (native M(r) 125,000), was partially purified from lobster muscle; enzyme activity coeluted with a 60-kDa polypeptide using anion-exchange chromatography. The 60-kDa protein reacted with a polyclonal antibody raised against a 20-amino acid peptide sequence found around the catalytic cysteine residue of mu- and m-calpains, but not with antibodies raised against other regions of mu- or m-calpain or with the anti-CDP IIb antibody. These results suggest that (1) the CDP IIb is the homolog of Drosophila calpain in crustaceans and (2) the active site regions of CDP IIa and mu- and m-calpains are similar.
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PMID:Immunological analysis of two calpain-like Ca2+-dependent proteinases from lobster striated muscles: relationship to mammalian and Drosophila calpains. 901 18

Major advances in the genetic understanding of the limb-girdle (LGMD) and congenital (CMD) muscular dystrophies have led to a new, genetically based classification of these disorders. The definition of the complex of dystrophin-associated proteins on a biochemical and subsequently genetic level has greatly accelerated this progress by providing candidate genes to complement or replace the process of linkage analysis either in families with muscular dystrophy or in sporadic cases. The major components of the dystrophin-associated proteins now known to be involved in muscular dystrophy besides dystrophin itself ar the sarcoglycan complex and the alpha 2-chain (merosin) of laminin-2 in the extracellular matrix. Mutations in the various sarcoglycans account for four types of autosomal recessive LGMD of varying severity (types 2C through 2F), including severe childhood-onset presentations. One type of autosomal recessive LGMD (type 2A) is caused by mutations in the protease calpain-3, whereas the gene for type 2B has not yet been identified, although the responsible locus has been assigned to chromosome 2p13. There are different autosomal dominant forms as well, one of which has been mapped to chromosome 5q31. With regard to CMDs, the major breakthrough involves a type of "classic" CMD with abnormalities of the white matter on magnetic resonance imaging of the brain. These patients show deficiencies of the laminin alpha 2-chain, and mutations in the corresponding gene have been identified. The group of laminin alpha 2-chain-positive classic CMD likely is heterogeneous. Among the group of CMDs with abnormalities of brain formation and mental retardation, genetic, immunohistochemical, and clinical differences are now beginning to emerge to help in the distinction between Fukuyama muscular dystrophy, the Walker-Warburg syndrome, and muscle-eye-brain disease.
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PMID:Beyond dystrophin: current progress in the muscular dystrophies. 901 40

Erb's type limb-girdle muscular dystrophy (LGMD) was identified and clinically studied in detail in a small community living in the Reunion Island (RI). It was linked to chromosome 15q and related to mutations in the muscle specific calpain 3 gene. A series of cases were afterwards clinically and genetically identified in the French metropolitan community. The phenotype was identical to the RI type in the great majority of cases, although clinical differences were noticed in a few cases. Six different mutations were identified in the RI families, whereas a series of 39 mutations were detected in the French metropolitan families, all different from those present in the RI patients. Phenotype-genotype correlations were attempted in both communities.
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PMID:Chromosome 15-linked limb-girdle muscular dystrophy: clinical phenotypes in Reunion Island and French metropolitan communities. 902 54


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