Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Annexins are a superfamily of calcium-dependent membrane-associated proteins which interact with phospholipids. The primary structure of Annexins I, III, VII, VIII and XI contain a region enriched in proline, glutamate, serine and threonine (PEST sequences) towards the N-terminal end while annexins II, V and VI possess PEST regions somewhat distal to the N-terminus. These PEST sequences are believed to be the signals for rapid intracellular degradation. Annexin I is known to be cleaved by calpain near its PEST region suggesting that its PEST region might be a possible calpain recognition site. Western blot analysis of annexins V and XI in rat lung homogenates suggest that these proteins are resistant to proteolysis by calpain. Annexin V was found to be stable to intrinsic lung proteases in the presence of either Ca2+ or EGTA while annexin XI was found to be partially degraded by intrinsic lung proteases in the presence of EGTA. Eight of the 10 known mammalian annexins also contain a pentapeptide sequence that is biochemically related to the KFERQ motif which is a known signal that targets protein for lysosomal proteolysis. Our data suggest that the annexins may be regulated by limited proteolysis, most likely at their N-terminal end, while most, if not all, of them might be degraded by the lysosomal pathway.
Mol Cell Biochem 2002 Feb
PMID:Proteolytic signals in the primary structure of annexins. 1195 51

Many studies have demonstrated that the calcium-dependent proteolytic system (calpains and calpastatin) is involved in myoblast differentiation. It is also known that myogenic differentiation can be studied in vitro. In the present experiments, using a mouse muscle cell line (C2C12) we have analyzed both the sequences of appearance and the expression profiles of calpains 1, 2, 3 and calpastatin during the course of myoblast differentiation. Our results mainly show that the expression of ubiquitous calpains (calpain 1 and 2) and muscle-specific calpain (calpain 3) at the mRNAs level as well as at the protein level do not change significantly all along this biological process. In the same time, the specific inhibitor of ubiquitous calpains, calpastatin, presents a stable expression at mRNAs level as well as protein level, all along myoblast to myotube transition. A comparison with other myogenic cells is presented.
Mol Cell Biochem 2002 Feb
PMID:Characterization of the calcium-dependent proteolytic system in a mouse muscle cell line. 1195 56

Previously we isolated a micro-calpain/PKCalpha complex from skeletal muscle which suggested tight interactions between the Ca2+-dependent protease and the kinase in this tissue. Our previous studies also underlined the involvement of ubiquitous calpains in muscular fusion and differentiation. In order to precise the relationships between PKCalpha and ubiquitous calpains in muscle cells, the expression of these two enzymes was first examined during myogenesis of embryonic myoblasts in culture. Our results show that calpains and PKCalpha are both present in myotubes and essentially localized in the cytosolic compartment. Moreover, calpains were mainly present after 40 h of cell differentiation concomitantly with a depletion of PKCalpha content in the particulate fraction and the appearance of PKMalpha fragment. These results suggest a possible calpain dependent down-regulation process of PKCalpha in our model at the time of intense fusion. In our experimental conditions phorbol myristate acetate (PMA) induced a rapid depletion of PKCalpha in the cytosolic fraction and its translocation toward the particulate fraction. Long term exposure of myotubes in the presence of PMA induced down-regulation of PKCalpha, this process being partially blocked by calpain inhibitors (CS peptide and inhibitor II) and antisense oligonucleotides for the two major ubiquitous calpain isoforms (m- and micro-calpains). Taken together, our findings argue for an involvement of calpains in the differentiation of embryonic myoblasts by limited proteolytic cleavage of PKCalpha.
Mol Cell Biochem 2002 Feb
PMID:Protein kinase Calpha is a calpain target in cultured embryonic muscle cells. 1195 72

Spectrins, components of the membrane skeleton, are implicated in various cellular functions. Understanding the diversity of these functions requires better characterization of the interacting domains of spectrins, such as the SH3 domain. Yeast two-hybrid screening of a kidney cDNA library revealed that the SH3 domain of alpha II-spectrin binds specifically isoform A of low-molecular-weight phosphotyrosine phosphatase (LMW-PTP). The alpha II-spectrin SH3 domain does not interact with LMW-PTP B or C nor does LMW-PTP A interact with the alpha I-spectrin SH3 domain. The interaction of spectrin with LMW-PTP A led us to look for a tyrosine-phosphorylated residue in alpha II-spectrin. Western blotting showed that alpha II-spectrin is tyrosine phosphorylated in vivo. Using mutagenesis on recombinant peptides, we identified the residue Y1176 located in the calpain cleavage site of alpha II-spectrin, near the SH3 domain, as an in vitro substrate for Src kinase and LMW-PTP A. This Y1176 residue is also an in vivo target for kinases and phosphatases in COS cells. Phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro. Similarly, the presence of phosphatase inhibitors in cell culture is associated with the absence of spectrin cleavage products. This suggests that the Y1176 phosphorylation state could modulate spectrin cleavage by calpain and may play an important role during membrane skeleton remodeling.
Mol Cell Biol 2002 May
PMID:Tyrosine phosphorylation regulates alpha II spectrin cleavage by calpain. 1197 83

Calsenilin (also called DREAM and KChIP3), a member of the neuronal calcium sensor family, was isolated in a yeast two-hybrid screen using an apoptotic domain of presenilin 2 as bait. Calsenilin is a cytoplasmic protein, but interacts with the COOH-termini of both presenilin 1 and presenilin 2 at the endoplasmic reticulum and the Golgi apparatus. In this study, we have investigated calsenilin's effect on apoptosis. In stable neuroglioma cell lines, we observed that calsenilin enhances apoptosis in response to serum withdrawal or thapsigargin. Consistent with these observations, caspase and apparently calpain activities were increased during apoptosis in calsenilin-overexpressing cells. Moreover, using calcium imaging we were able to show that cells treated with thapsigargin released more calcium from intracellular stores when calsenilin was overexpressed. Taken together, these data suggest that calsenilin causes cells to be more susceptible to apoptotic triggers, possibly by altering calcium dynamics.
Mol Cell Neurosci 2002 Apr
PMID:Calsenilin enhances apoptosis by altering endoplasmic reticulum calcium signaling. 1198 22

The present study was designed to investigate the possible effects of chronic dichlorvos exposure on the various aspects of calcium homeostasis in rat brain. Chronic dichlorvos administration caused significant rise in the intrasynaptosomal calcium levels. The activity of major calcium expelling enzyme i.e. Ca2+ATPase was found to be declined. Also, the depolarization induced calcium uptake via voltage operated calcium channels increased significantly. Concomitant to the increase in intrasynaptosomal calcium, calpain activity was found to be increased. The results presented herein, indicate that the toxic effects of dichlorvos could be mediated through modifications in the intracellular calcium homeostasis which may lead to impaired neuronal function.
Mol Cell Biochem 2002 Mar
PMID:Calcium homeostasis and dichlorvos induced neurotoxicity in rat brain. 1203 Mar 70

In light of evidence of linkage of obesity to chromosome 2q31-q37, we hypothesized that the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus (NIDDM) is involved in early onset obesity. We screened the NIDDM 'high-risk'-haplotype combination formed by the alleles 112 and 121 of the polymorphisms UCSNP-43, -19, and -63 in 166 families consisting of an extremely obese child or adolescent (mean BMI percentile: 99.3+/-1.38), one or more obese sibs (mean BMI percentile: 97.42+/-2.88), and both of their parents. Genotyping for three calpain-10 gene polymorphisms was performed by polymerase chain reaction (PCR) with (a) length polymorphism detection (UCSNP-19) or (b) allele-specific PCR (UCSNP-43 and -63). To allow for correct haplotype assignment all individuals were additionally genotyped for two microsatellite markers (D2S125 and D2S2338). We followed a hierarchical test procedure. As the first step, model-free linkage analysis was performed using maximum likelihood binomial statistics. The second stage consisted of a one-sided asymptotic pedigree disequilibrium test for the UCSNP-43 and on an exploratory level for the other SNP-markers and all haplotypes formed by the three SNPs. The final stage investigated the reported haplotype combination. We failed to detect an initial linkage of obesity to this region (LOD score <0.4). All subsequent exploratory analyses were negative. Our analysis of the relationship between the NIDDM 'high-risk' haplotype combination and extreme early onset obesity revealed no evidence for linkage and association.
Mol Genet Metab 2002 Jun
PMID:No evidence for involvement of the calpain-10 gene 'high-risk' haplotype combination for non-insulin-dependent diabetes mellitus in early onset obesity. 1208 14

Molecular chaperone activity of lens alpha-crystallins is reduced by loss of the C terminus. The purpose of this experiment was to 1) determine the cleavage sites produced in vitro by ubiquitous m-calpain and lens-specific Lp82 on alpha-crystallins, 2) identify alpha-crystallin cleavage sites produced in vivo during maturation and cataract formation in rat lens, and 3) estimate the relative activities of Lp82 and m-calpain by appearance of protease-specific cleavage products in vivo. Total soluble protein from young rat lens was incubated with recombinant m-calpain or Lp82 and 2 mM Ca2+. Resulting fragmented alpha-crystallins were separated by two-dimensional gel electrophoresis. Eluted alpha-crystallin spots were analyzed by mass spectrometry. Cleavage sites on insoluble alpha-crystallins were determined similarly in mature rat lens nucleus and in cataractous rat lens nucleus induced by selenite. In vitro proteolysis of alphaA-crystallin by Lp82 and m-calpain produced unique cleavage sites by removing 5 and 11 residues, respectively, from the C terminus. In vivo, the protease-specific truncations removing 5 and 11 residues from alphaA were both found in maturing lens, whereas only the truncation removing 5 residues was found in cataractous lens. Other truncation sites, common to both calpain isoforms, resulted from the removal of 8, 10, 16, 17, and 22 residues from the C terminus of alphaA. Using uniquely truncated alphaA-crystallins as in vivo markers, Lp82 and m-calpain were both found to be active during normal maturation of rat lens, whereas Lp82 seemed especially active during selenite cataract formation. These C-terminal truncations decrease chaperone activity of alpha-crystallins, possibly leading to the observed increases in insoluble proteins during aging and cataract. The methodology that allowed accurate mass measurements of proteins eluted from 2D gels should be useful to examine rapidly other post-translational modifications.
Mol Cell Proteomics 2002 May
PMID:Mass measurements of C-terminally truncated alpha-crystallins from two-dimensional gels identify Lp82 as a major endopeptidase in rat lens. 1211 77

G protein-coupled receptor kinase (GRK) 2 plays a crucial role in regulating the extent of desensitization and resensitization of G protein-coupled receptors (GPCRs). We have shown that the expression level of GRK2 in lymphocytes decreases during inflammatory diseases such as arthritis. Reactive oxygen species play an important role in a variety of inflammatory conditions, including arthritis. We demonstrate herein that oxidative stress, induced by exposure of lymphocytes to H(2)O(2), results in a 50% reduction in GRK2 protein levels and GRK activity with no changes in mRNA expression. Treatment of lymphocytes with the tyrosine kinase inhibitor genistein partially reverses the effect of H(2)O(2) on GRK2 levels, although we did not detect direct tyrosine phosphorylation of GRK2. Inhibition of the nonproteasomal protease calpain by calpeptin can prevent the H(2)O(2)-induced GRK2 decrease. In vitro experiments confirm that GRK2 is partially digested by m-calpain in a calcium-dependent way. Functionally, H(2)O(2)-induced decrease in GRK2 levels is associated with an ~70% decrease in agonist-induced beta(2)-adrenergic receptor sequestration. We describe oxidative stress as a novel mechanism for regulation of the intracellular level of GRK2 during inflammatory processes. Moreover, our data demonstrate that oxidative stress may change the functioning of GPCRs via calpain-dependent regulation of GRK2 levels.
Mol Pharmacol 2002 Aug
PMID:Oxidative stress decreases G protein-coupled receptor kinase 2 in lymphocytes via a calpain-dependent mechanism. 1213 Jun 91

Activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's disease (AD) (Liu et al., 1999; Rapoport, 1999; Selkoe, 1994). Calpains regulate the function of many proteins by limited proteolysis and initiate the complete degradation of other proteins. In particular, they modulate processes that govern the function and metabolism of proteins key to the pathogenesis of AD, including tau and amyloid precursor protein (APP). (Xie and Johnson, 1998; Wang, 2000). We have found that overexpression of APP(K670M:N671L) and PS1(M146L) proteins in hippocampal cultures derived from transgenic mice causes an increase in the frequency of spontaneous release of neurotransmitter. We have also found that calpain immunoreactive clusters are co-localized with immunoreactivity for the vesicle-associated presynaptic marker, synaptophysin. Moreover, application of calpain inhibitor reduces the frequency of spontaneous release of neurotransmitter. Therefore, we have hypothesized that calpains might contribute to the increase in transmitter release. Based on this hypothesis, we propose to test whether it is possible to restore normal synaptic transmission between cells derived from the transgenic model of AD by using calpain inhibitors. The transgenic mouse model also shows spatial learning impairment, a phenomenon that is thought to be associated with plastic changes at synaptic level. Therefore, we will also test whether we can rescue the learning impairment through a treatment with calpain inhibitors.
J Mol Neurosci
PMID:Calpain inhibitors: a treatment for Alzheimer's disease. 1221 71


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