Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat skeletal muscle calpastatin form is markedly modified in its inhibitory properties by means of a reverse reaction which involves both phosphorylation and dephosphorylation. Dephospho-calpastatin shows greater inhibitory efficiency versus mu-calpain, whereas phospho-calpastatin shows maximal inhibition versus m-calpain. Both forms are present in fresh rat muscle. Phosphorylation has been reproduced "in vitro" using a homologous Ca2+ independent protein kinase and found to result in the incorporation of approximately one mole of 32P per mole of protein. Dephosphorylation was induced by treatment with alkaline phosphatase and 32P release shown found to correlate with modifications of the inhibitory properties. This reversible covalent modification of calpastatin is considered an important advancement in the understanding of how different calpain isoforms can be more efficiently controlled by a single inhibitor isozyme form.
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PMID:Modulation of inhibitory efficiency of rat skeletal muscle calpastatin by phosphorylation. 153 Jun 32

The degradation of troponin (Tn) subunits by calpain was studied by incubating either isolated cardiac Tns or myocardial cryosections with two different calpain isoenzymes isolated from rat skeletal muscle. Western-blot analysis with monoclonal antibodies against TnI and TnT showed that mu-calpain was at least ten times more active than m-calpain in degrading TnI and TnT both in vitro and in situ. TnC was completely resistant to both proteinase forms. Phosphorylation by cyclic AMP-dependent protein kinase (PKA) isolated from rat skeletal muscle reduced the sensitivity of TnI to degradation. This effect in combination with an increased efficiency of the endogenous inhibitor [Salamino, De Tullio, Michetti, Mengotti, Melloni and Pontremoli (1994) Biochem. Biophys. Res. Commun. 199, 1326-1332] probably reduces the proteolytic activity of calpain in cells on PKA stimulation. Conversely, phosphorylation by protein kinase C (PKC) resulted in a twofold increase in the degradation of TnI. Degradation by m-calpain was not modified by Tn phosphorylation. The different sensitivity to mu-calpain might be related to changes in TnI oligomeric structure. Indeed, on PKC phosphorylation, the apparent molecular mass of TnI calculated from the distribution coefficient of Tn complex in Sephadex G-100 matrix was reduced from 90 to 30 kDa suggesting dissociation of the Tn complex.
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PMID:Specific degradation of troponin T and I by mu-calpain and its modulation by substrate phosphorylation. 775 88

Two calpastatins, with Mr 110 KD and named calpastatin I and II, have been isolated from rat heart and kidney and displayed distinct inhibitory efficiency with mu- and m-calpain, respectively, as those isolated from rat skeletal muscle. Whereas the level of calpastatin I always exceeds that of mu-calpain, the level of calpastatin II appears to be more closely correlated to the level of m-calpain. As previously shown for skeletal muscle, the two inhibitor proteins can be interconverted by a phosphorylation-dephosphorylation reaction; the enzyme responsible for phosphate incorporation in calpastatin I is now identified in c-AMP dependent protein kinase A. In rat erythrocytes, containing a single calpain form, the single low Mr calpastatin form does not undergo reversible phosphorylation and is equally efficient in respect to typical mu- and m-calpain. The presence of two interconvertible calpastatin forms provides the cells with a highly sensitive mechanism of regulation of the Ca(2+)-dependent proteolytic system.
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PMID:Modulation of calpastatin specificity in rat tissues by reversible phosphorylation and dephosphorylation. 814 76

Isolated connexin-32s from rat and mouse liver are proteolyzed in vitro by the intracellular Ca(2+)-dependent neutral proteases, mu-calpain and m-calpain, producing a major fragment of 26 kDa. Connexin-26 is not proteolyzed by calpain. Calpain cleaves connexin-32 at its C-terminal end as shown by 125I-calmodulin binding experiments. Connexin-32, but not connexin-26, is phosphorylated by both protein kinase A and protein kinase C in serine residues and the sites of phosphorylation by both kinases remain in the major 26-kDa fragment resulting from calpain proteolysis. Phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, prevents the proteolytic attack of mu-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, alpha-chymotrypsin, proteinase K, and trypsin.
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PMID:Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. 839 Sep 88

Phosphorylation by adenosine-3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA), but not by Ca(++)-calmodulin-dependent protein kinase II (CaMK II), was shown earlier to protect microtubule-associated protein 2 (MAP2) from cleavage by m-calpain (Johnson and Foley: J Neurosci Res 34: 642-647, 1993). We reinvestigated this phenomenon with the physiologically more relevant mu-calpain and found a qualitatively similar but quantitatively different picture. We further demonstrate that 1) protection is biphasically dependent on the degree of phosphorylation; 2) Ca(++)-phospholipid-dependent protein kinase (PKC) has about the same effect as PKA; 3) the effects of kinases A and C are not additive; and 4) stripping of native MAP2 from its phosphate content (17.8 +/- 2.3 mol/mol) enhances calpainolysis 3.6-fold. A reciprocal effect between kinase A and MAP2 was found: the RII, but not the RI, regulatory subunit of kinase A, which was shown to bind specifically to MAP2, is protected by MAP2 from mu-calpain attack. It is suggested that the specific anchoring of kinase A-II on MAP2 may serve not only kinase targeting in the dendrites, but also protection from calpainolytic degradation.
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PMID:Mutual protection of microtubule-associated protein 2 (MAP2) and cyclic AMP-dependent protein kinase II against mu-calpain. 877 65

Subarachnoid hemorrhage (SAH) often leads to a long-term narrowing of cerebra! artery called vasospasm. To understand the molecular mechanisms in vasospasm, signal transduction of tyrosine kinase pathway and phosphorylation of myosin light chain (MLC) and calponin (CaP) in the basilar artery were studied. Vasospasm was produced in the canine basilar artery by a two-hemorrhage method, and vasocontraction was induced by a local application of KCI or serotonin to the basilar artery after a transclival exposure. Intracellular substrates of tyrosine kinase pathway, including Shc, Rafl, and extracellular-regulated kinases in the basilar artery, were activated after SAH, and the activation of Shc suggests stimulation of signal transductions from tyrosine kinase receptors, G-coupled receptors, or both. The activation of tyrosine kinase pathway in vasospasm also was supported by dose-dependent dilation of the spastic basilar artery on days 0 and 7 by topical application of genistein, a tyrosine kinase inhibitor, and associated marked inhibition of tyrosine phosphorylation of intracellular substrates, including Shc. In addition, the generation of protein kinase M, catalytic fragment of protein kinase C(alpha) (PKC alpha), in vasospasm on days 0 and 7 was inhibited in response to genistein, indicating an inactivation of mu-calpain. It is suggested, therefore, that the reversal of vasospasm by genistein is closely associated with the restoration of intracellular Ca2+ levels. However, the increased activities of Raf1 and extracellular-regulated kinases in vasospasm were declined on day 7 compared with those on day 0 or 2, suggesting that the activation of tyrosine kinase pathway is more closely associated with the early stage of vasospasm than with the late stage of vasospasm. The analysis by pyrophosphate polyacrylamide gel electrophoresis (PPi-PAGE) demonstrated three MLC bands in vasospasm on days 2 and 7, as well as in KCI- and serotonin-induced vasocontraction. Since PPi-PAGE resolves smooth muscle MLC into three bands in the MLC kinase (MLCK)-mediated phosphorylation and into a single band in the PKC-mediated phosphorylation based on the phosphorylation state, the current results suggest that MLC in vasospasm is phosphorylated by MLCK but not by PKC. In basilar artery, CaP was significantly down-regulated, and in addition, significantly phosphorylated on serine and threonine residues only in vasospasm on days 2 and 7. Although the significance of CaP phosphorylations in vivo still is controversial, CaP down-regulation and phosphorylation may attenuate the inhibition of Mg(2+)-ATPase activity by CaP and induce a potential enhancement of smooth muscle contractility in delayed vasospasm. Since CaP is phosphorylated in vivo by PKC, activated PKC in vasospasm may phosphorylate CaP. Thus, SAH stimulates tyrosine kinase pathway to increase intracellular Ca2+ and activate PKC, and the former activates MLCK to phosphorylate MLC, whereas the latter phosphorylates CaP but not MLC.
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PMID:Activation of protein kinases in canine basilar artery in vasospasm. 988 54

Human RSa cells are highly sensitive to apoptotic-like cell death by ultraviolet irradiation (UV) while UVr-1 cells are their variant with an increased resistance to UV. Three days after UV at 10 J/m2, the viability of RSa cells was approximately 17% while that of UVr-1 cells was 65%. This different survival might reflect apoptotic cell death since apoptosis-specific DNA ladder was more clearly observed in RSa cells than in UVr-1 cells after UV. Addition of ALLN/calpain inhibitor I to the culture medium after UV resulted in similar survival (14 - 18%) between RSa and UVr-1 cells. Immunoblot analysis showed down-regulation of protein kinase CTheta, Src, Bax and mu-calpain after UV was more prominent in UVr-1 than in RSa cells. Activated mu-calpain appeared within 1 h post-UV only in UVr-1 cells. The expression of calpastatin, a specific endogenous inhibitor of calpain, was higher in RSa than in UVr-1 cells. To further examine the role of calpain in UV-induced cell death, cDNA of human calpastatin was transfected into UVr-1 cells. The results showed that overexpression of calpastatin suppressed down-regulation of Src, mu-calpain and Bax. Concomitantly, colony survival after UV was reduced in calpastatin-transfected cells as compared to vector control cells. Our results suggest that activation of calpain might account for, at least in part, the lower susceptibility to UV-induced cell death in UVr-1 cells.
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PMID:Increase in ultraviolet sensitivity by overexpression of calpastatin in ultraviolet-resistant UVr-1 cells derived from ultraviolet-sensitive human RSa cells. 1082 76

Rapid IkappaBalpha turnover has been implicated in the high basal NF-kappaB activity in WEHI 231 B immature IgM(+) B cells. Here we show that treatment of WEHI 231 cells with apigenin, a selective inhibitor of the protein kinase CK2, decreased the rate of IkappaBalpha turnover and nuclear levels of NF-kappaB. Turnover of IkappaBalpha in these cells is mediated in part by the protease calpain. Since both CK2 and calpain target the proline-glutamic acid-serine-threonine (PEST) domain, we investigated the role of CK2 in the degradation of IkappaBalpha by calpain using an in vitro phosphorylation/degradation assay. CK2 phosphorylation enhanced mu-calpain-mediated degradation of wild-type IkappaBalpha, but not of mutant 3CIkappaBalpha, with S283A, T291A, and T299A mutations in phosphorylation sites within the PEST domain. Roles for CK2 and calpain in IkappaBalpha turnover were similarly shown in CH31 immature and CH12 mature IgM(+) B cells, but not in A20 and M12 IgG(+) B cells. These findings demonstrate for the first time that CK2 phosphorylation of serine/threonine residues in the PEST domain promotes calpain-mediated degradation of IkappaBalpha and thereby increases basal NF-kappaB levels in IgM(+) B cells.
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PMID:Phosphorylation by the protein kinase CK2 promotes calpain-mediated degradation of IkappaBalpha. 1167 97

Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.
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PMID:Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation. 1263 47

Calpains are intracellular Ca2+-dependent cysteine proteases that are released in the extracellular milieu by tubular epithelial cells following renal ischemia. Here we show that externalized calpains increase epithelial cell mobility and thus are critical for tubule repair. In vitro, exposure of human tubular epithelial cells (HK-2 cells) to mu-calpain limited their adhesion to extracellular matrix and increased their mobility. Calpains acted primarily by promoting the cleavage of fibronectin, thus preventing fibronectin binding to the integrin alphavbeta3. Analyzing downstream integrin effects, we found that the cyclic AMP-dependent protein kinase A pathway was activated in response to alphavbeta3 disengagement and was essential for calpain-mediated increase in HK-2 cell mobility. In a murine model of ischemic acute renal failure, injection of a fragment of calpastatin, which specifically blocked calpain activity in extracellular milieu, markedly delayed tubule repair, increasing functional and histological lesions after 24 and 48 h of reperfusion. These findings suggest that externalized calpains are critical for tubule repair process in acute renal failure.
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PMID:Extracellular calpains increase tubular epithelial cell mobility. Implications for kidney repair after ischemia. 1682 70


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