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)

The Caenorhabditis elegans gene unc-22 encodes a very large muscle protein, called twitchin, which consists of a protein kinase domain and several copies of two short motifs. The sequence of twitchin has unexpected similarities to the sequences of proteins of the immunoglobulin superfamily, cell adhesion molecules and vertebrate muscle proteins, including myosin light-chain kinase. These homologies, together with results from earlier genetic and molecular analyses, indicate that twitchin is involved in a novel mechanism of myosin regulation.
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PMID:Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans. 281 2

Rat hearts perfused with 32Pi were made hypoxic by perfusion with medium gassed with N2/CO2 (19:1). There was a rapid decrease in tension development (25% of control within 40 s), but little change in the frequency of contraction, time to peak tension, or rate of relaxation. The phosphorylation of troponin-I, C-protein and myosin P-light chain was unaffected by 5 min of hypoxia, whereas the proportions of glycogen phosphorylase and pyruvate dehydrogenase in the active form increased slowly. When aerobically perfused hearts were challenged with a bolus (70 pmole) of D,L-isoprenaline, there was a large increase in contractile force, cyclic AMP concentration, phosphorylation of troponin-I and C-protein and activation of phosphorylase and pyruvate dehydrogenase. Hypoxia for 5 min caused a slight, progressive decrease in the response to isoprenaline of force, cyclic AMP and activation of phosphorylase and pyruvate dehydrogenase. In contrast, there was a larger decrease in the phosphorylation of troponin-I and C-protein, suggesting that the activity of cyclic AMP-dependent protein kinase towards the contractile proteins may be impaired by hypoxia. The phosphorylation of myosin P-light chain was unaltered by any condition. The response to hypoxia is compared to that of ischaemia, where a complete loss of the response to isoprenaline occurs after 5 min.
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PMID:The effect of hypoxia on the phosphorylation of contractile and other proteins in perfused rat heart challenged by isoprenaline. 282 35

The activities of some proteins involved in the process of contraction-relaxation in smooth muscle cells are regulated by reversible phosphorylation. Phosphorylation of myosin by MLCK has been shown to be a pre-requisite for muscle contraction. MLCK, itself, is a substrate for cAMP-dependent protein kinase. Relaxation is favored in the event that MLCK is phosphorylated by cAMP-dependent protein kinase because this modification inhibits the activity of MLCK. In our attempt to understand the mechanism and regulation of contractile activity in smooth muscle cells, we purified and characterized the enzymes which catalyze the dephosphorylation of myosin and MLCK. We have purified 3 smooth muscle phosphatases termed SMP-I, II and IV to apparent homogeneity and partially purified SMP-III from turkey gizzards. Characterization of these enzymes revealed that they are distinct. They have different physical, enzymatic and immunological properties. As isolated, all 4 enzymes dephosphorylate myosin light chains rapidly but only SMP-III and IV are active toward myosin or heavy meromyosin. However, SMP-I could be activated toward myosin when its catalytic subunit is dissociated from the regulatory subunits and when the 55,000-Da regulatory subunit is digested or released from the holoenzyme. Recently we have purified to apparent homogeneity 2 protein phosphatases from rabbit uterine muscle. Partial characterization of these enzymes revealed their close similarity to the avian smooth muscle phosphatases. Analysis of the properties of the smooth muscle phosphatases led us to speculate on their function in vivo. SMP-III and IV are most likely to dephosphorylate myosin to cause relaxation because they exhibit the highest activity toward intact myosin. SMP-I may play a role in this process if there is a physiological mechanism which dissociates the catalytic subunit from the 55,000-Da regulatory subunit or from both regulatory subunits. A more obvious role for SMP-I is to dephosphorylate MLCK following phosphorylation by cAMP-dependent protein kinase to restore the high activity of MLCK. SMP-II does not dephosphorylate myosin and has low activity toward MLCK. It is active toward glycogen synthase suggesting a role in glycogen metabolism for the production ATP required to supply the energy for contraction. We are currently undertaking experiments to verify these proposals.
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PMID:Characterization of the smooth muscle phosphatases and study of their function. 282 8

Previously, we have shown that okadaic acid (OA), isolated from black sponge (Halichondria okadai) causes contraction even in the absence of Ca++ in the saponin-permealized taenia isolated from guinea pig cecum. In the present study, mechanism of action of OA was examined using native actomyosin extracted from chicken gizzard smooth muscle. In the absence of Ca++, OA (0.1-1 microM) induced superprecipitation and increased the Mg++-adenosine triphosphatase activity. The OA-induced superprecipitation was enhanced by Ca++ at a concentration (greater than 0.1 microM) which did not activate the calmodulin-dependent myosin light chain (MLC) kinase. The effect of OA was not affected by the calmodulin inhibitor, trifluoperazine, at a concentration (100 microM) needed to inhibit the Ca++-induced response, but was inhibited markedly by the nonselective kinase inhibitors, amiloride (1 mM) and K-252a (5 microM). The OA-induced superprecipitation in the absence of Ca++ was accompanied by phosphorylation of the 20 K dalton MLC, which also was enhanced by low concentration of Ca++ (greater than 0.1 microM). OA did not change the phosphatase activity which dephosphorylates the phosphorylated MLC. An activator of Ca++- and phospholipid-dependent protein kinase, 12-O-tetradecanoylphorbol 13-acetate (1 microM), did not modulate superprecipitation or phosphorylation of MLC in the presence and absence of OA. Furthermore, inhibitors of Ca++ and phospholipid-dependent protein kinase, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride (400 microM) and polymyxin B (100 micrograms/ml), affected neither superprecipitation nor phosphorylation of MLC induced by OA. With a reconstituted system containing purified myosin and MLC kinase, OA induced only slight phosphorylation of MLC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium-independent phosphorylation of smooth muscle myosin light chain by okadaic acid isolated from black sponge (Halichondria okadai). 282 58

A cAMP-dependent regulatory protein which modulates the phosphorylation of scallop myosin regulatory light chain-a (RLC-a) by RLC-a myosin kinase (aMK) (Sohma, H. & Morita, F. (1986) J. Biochem. 100, 1155-1163) was purified from the scallop smooth muscle. RLC-a is abundant in the opaque portion of scallop smooth muscle, one of the catch muscles. The regulatory protein for aMK was purified by employing successively DEAE Toyopearl ion exchange chromatography, Sepharose 4B-8(6-aminohexylamino)cAMP affinity chromatography, and Sephadex G 100 gel filtration. The molecular mass of the regulatory protein was 41 kDa, based on the mobility in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. With increasing amounts of the regulatory protein, the aMK activity decreased, and complete inhibition was observed at the concentration of twice that of aMK. The aMK activity inhibited by the regulatory protein was restored by the addition of cAMP. These results suggest that aMK is similar to a catalytic subunit of cAMP-dependent protein kinase, and the protein reported here is similar to its regulatory subunit. aMK may exist as an inactive form, as a combination with this regulatory protein, in vivo and be deinhibited by an increase in the intracellular concentration of cAMP. We discuss a possible correlation between the phosphorylation of RLC-a in myosin catalyzed by aMK and the catch state of the opaque portion of scallop smooth muscle.
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PMID:A cAMP-dependent regulatory protein for RLC-a myosin kinase catalyzing the phosphorylation of scallop smooth muscle myosin light chain. 283 66

1. The myosin molecule from Ehrlich ascites tumour cells consists of heavy chains of about 200 kDa and three species of light chains of 20, 19 and 15 kDa. 2. The heavy chain can be phosphorylated in vitro either by endogenous Ca2+-independent kinase or by casein kinase II. 3. The 20 and 19 kDa light chains can be phosphorylated either by an endogenous kinase or by myosin light chain kinase from chicken gizzard. 4. The Ca2+-ATPase activity of the purified myosin was 0.3 mumol/min mg protein. The Mg2+-ATPase activity was activated 14-fold by actin upon the light chain phosphorylation.
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PMID:Purification of myosin from Ehrlich ascites tumour cells (phosphorylation of its light chain and heavy chain). 285 95

The effects of several antidepressant and antipsychotic agents on Ca2+-calmodulin-regulated myosin light chain phosphorylation were evaluated. At a concentration of 100 microM, the antidepressant agents buproprion, mianserin and maprotiline were ineffective; zimelidine, desipramine and imipramine produced 40-50% inhibition; and iprindole and fluoxetine produced 75-90% inhibition. The efficacies of iprindole and fluoxetine were similar to the phenothiazine antipsychotics chlorpromazine and trifluoperazine. Clozapine, an atypical antipsychotic and the butyrophenone haloperidol were relatively ineffective as myosin light chain phosphorylation inhibitors. IC50 values of the most effective agents were: trifluoperazine 16 microM, fluoxetine 28 microM, chlorpromazine and iprindole 56 microM. As with trifluoperazine, inhibition of myosin phosphorylation by iprindole was completely attenuated in the presence of exogenous calmodulin. However, a significant component (30%) of the inhibitory effect of fluoxetine was not reversible with calmodulin. These results show that some antidepressant agents, most notably iprindole and fluoxetine, are capable of antagonizing a calmodulin-regulated protein kinase through calmodulin inhibition; and in the case of fluoxetine, through an additional calmodulin-independent mechanism.
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PMID:Antidepressants and protein kinases: inhibition of Ca2+-regulated myosin phosphorylation by fluoxetine and iprindole. 286 58

Actomyosin in smooth muscle is in a quiescent state. The mechanism or mechanisms by which Ca2+ activates the actomyosin ATPase is not clear. There is sufficient evidence for the presence of enzyme systems which phosphorylate and dephosphorylate myosin light chains. The activity of the kinase that phosphorylates the myosin is regulated by cAMP-dependent protein kinase. Phosphorylated kinase has decreased affinity for calmodulin and lower activity when compared with unphosphorylated myosin light chain kinase. The activity of myosin light chain kinase is also regulated by calcium-calmodulin. In the presence of Ca2+, myosin is phosphorylated. In the absence of Ca2+, the phosphatase activity becomes dominant; the myosin remains in the unphosphorylated form under this condition. The Mg2+-ATPase of the phosphorylated myosin is activated by actin. The maximal activation of the Mg2+-ATPase by actin requires Ca2+ and tropomyosin, a protein located on the thin filament. Hence, the actin-activation of the Mg2+-ATPase requires Ca2+ even after phosphorylation by the calcium-calmodulin dependent kinase. The regulation of actin-activated ATPase activity by myosin light chain phosphorylation is depicted in the schematic diagram. Caldesmon, an actin-binding protein which also binds to calmodulin in the presence of Ca2+, has been shown to be present in thin-filaments isolated from smooth muscle. This protein inhibits actin-activated myosin ATPase activity. The release from this inhibition requires Ca2+ and calmodulin. The possibility that caldesmon is also involved in the calcium regulation of actomyosin in smooth muscle is presently under investigation in a number of laboratories.
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PMID:Regulation of actomyosin ATPase in smooth muscle. 294 44

Phospholamban, the putative regulatory proteolipid of the Ca2+/Mg2+ ATPase in cardiac sarcoplasmic reticulum, was selectively phosphorylated by a Ca2+/calmodulin (CaM)-dependent protein kinase associated with a cardiac membrane preparation. This kinase also catalyzed the phosphorylation of two exogenous proteins known to be phosphorylated by the multifunctional Ca2+/CaM-dependent protein kinase II (Ca2+/CaM-kinase II), i.e., smooth muscle myosin light chains and glycogen synthase a. The latter protein was phosphorylated at sites previously shown to be phosphorylated by the purified multifunctional Ca2+/CaM-kinase II from liver and brain. The membrane-bound kinase did not phosphorylate phosphorylase b or cardiac myosin light chains, although these proteins were phosphorylated by appropriate, specific calmodulin-dependent protein kinases added exogenously. In addition to phospholamban, several other membrane-associated proteins were phosphorylated in a calmodulin-dependent manner. The principal one exhibited a Mr of approximately 56,000, a value similar to that of the major protein (57,000) in a partially purified preparation of Ca2+/CaM-kinase II from the soluble fraction of canine heart that was autophosphorylated in a calmodulin-dependent manner. These data indicate that the membrane-bound, calmodulin-dependent protein kinase that phosphorylates phospholamban in cardiac membranes is not a specific calmodulin-dependent kinase, but resembles the multifunctional Ca2+/CaM-kinase II. Our data indicate that this kinase may be present in both the particulate and soluble fractions of canine heart.
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PMID:Identification of membrane-bound calcium, calmodulin-dependent protein kinase II in canine heart. 295 8

Rabbit brain actomyosin showed several fold stimulation of the MgATPase activity by Ca2+ alone and by Ca2+/calmodulin. The calmodulin-binding drug, fluphenazine, abolished the stimulated activity. In the presence of Ca2+, exogenous calmodulin had a biphasic effect on ATPase activity at low concentrations (less than 0.15 microM) and activated the ATPase activity by 60-70% at about 1 microM. Tropomyosin-troponin complex from skeletal muscle did not stimulate the ATPase activity of brain actomyosin, but conferred Ca2+ sensitivity to a skeletal muscle myosin/brain actomyosin mixture. These results indicate the presence of myosin-linked, calmodulin-dependent, Ca2+-regulatory system for brain actomyosin. Heavy and light chains of brain myosin were found to be rapidly phosphorylated by endogenous Ca2+-dependent protein kinase(s). Ca2+-independent phosphorylation of one of the light chains was also observed.
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PMID:Calcium/calmodulin regulation of ATPase activity and endogenous phosphorylation of mammalian brain actomyosin. 295 83


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