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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the roles of protein phosphatases type 1 (PP1) and type 2A (PP2A) in 1,25-dihydroxy-cholecalciferol [1,25(OH)2D3]-induced differentiation of HL-60 cells into monocytes, we examined the enzyme activity and the protein and gene expressions of PP1 and PP2A in these cells. Calyculin-A augmented the 1,25(OH)2D3-induced differentiation of the cells. Treatment of the cells with 1,25(OH)2D3 led to a decrease in PP1-like activity in the cytosol fraction, with a concomitant increase in the membrane and nuclear PP1-like activity, as determined when protein phosphatase activity was assayed using myosin light chain as substrate in the presence of 5 nM okadaic acid. Western blot analysis with antibodies specific for PP1 catalytic subunit isozymes (PP1 alpha, PP1 gamma, and PP1 delta) showed that all three PP1 isozymes were expressed but were differentially distributed in each cellular fraction. Subcellular redistribution of PP1-like activity during 1,25(OH)2D3-induced differentiation was mainly attributed to PP1 gamma and PP1 alpha proteins. In contrast, the localizations of PP1 delta and PP2A catalytic and regulatory subunits were not significantly affected by 1,25(OH)2D3 treatment. The gene expressions of PP1 alpha and PP1 gamma appeared to be constant during processes of monocytic differentiation. The correlation between phenotypic and functional changes of HL-60 cells on the one hand and subcellular redistribution of PP1-like activity on the other suggest that the translocations of PP1 alpha and PP1 gamma isozymes may contribute to the 1,25(OH)2D3-induced monocytic differentiation of HL-60 cells.
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PMID:Translocation of protein phosphatase 1 catalytic subunits during 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL-60 cells. 785 Jul 88

The role of cyclic strain in the regulation of 20 kDa myosin light chain phosphorylation (MLC20) in cultured smooth muscle cells (SMC) is unknown. The objective of this study was to determine whether cyclic strain stimulates the dephosphorylation of MLC20 in serum-fed SMC displaying a high basal level of phosphorylation. Confluent bovine aortic SMC were subjected to 10% average strain at 60 cycles per minute for 30 and 60 minutes. Basal MLC20 phosphorylation (N = non,M = mono,D = di) of serum-fed SMC was as follows: N = 34%:M = 27%:D = 39%. After 60 min of cyclic strain, both mono and diphosphorylated MLC20 were decreased to 21 and 15% respectively. The strain-induced dephosphorylation of MLC20 was partially inhibited by the protein phosphatase 1/2A inhibitor, calyculin A (5 nM). However, phosphorylase a phosphatase activities in Triton-soluble and insoluble fractions of SMC were unaffected by cyclic strain. The data suggest that cyclic strain causes dephosphorylation of MLC20 in SMC which may be partially due to activation of MLC20 phosphatase and/or inhibition of MLC20 phosphorylation.
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PMID:Cyclic strain stimulates dephosphorylation of the 20kDa regulatory myosin light chain in vascular smooth muscle cells. 799 14

Protein phosphatase 2A (PP2A) is composed of structural (A), catalytic (C), and regulatory subunits (B). Immunological analyses identified B alpha/PR55 alpha as the major regulatory subunit of brain PP2A while a unique B' subunit was associated with the cardiac enzyme. Recombinant PP2A heterotrimers were purified from insect cells infected with baculoviruses expressing A and C, in combination with viruses expressing B alpha/PR55 alpha, B beta/PR55 beta, or SV40 small tumor antigen (st). Phosphatase activities of rAC-B alpha and rAC-B beta were similar to those for brain AC-B alpha, while rAC-st was 50-80% less active. Heparin had no effect on rAC-st myosin light chain phosphatase activity, while the B subunit-containing forms were stimulated 2-3-fold. Protamine caused a 3-4-fold increase in AC-B alpha and rAC-st activities and a marked activation of rAC-B beta (6-fold) and AC-B' (10.5-fold). When histone H1 was used as substrate, all of the heterotrimers were stimulated approximately 4-fold by heparin. The activity of AC-B' and rAC-B beta were increased 2-fold by Mn2+, while a 6-fold stimulation was observed with rAC-st. Chemical cross-linking of AC-B alpha and AC-B beta generated 200-kDa complexes, while AC-st was present as a 150-kDa complex. These results demonstrate that different regulatory proteins affect enzyme activity and the response to agents that modify PP2A activity in vitro. Different PP2A heterotrimers are likely to have distinct functions in vivo, and changes in subunit composition will have an important impact on signal transduction pathways.
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PMID:Comparison of heterotrimeric protein phosphatase 2A containing different B subunits. 805 Nov 2

Three molecular species of Mg(2+)-dependent protein phosphatase (MPPs-1, -2, and -3) were isolated by DEAE cellulose column chromatography and gel filtration from an extract of Saccharomyces cerevisiae. MPP-1 was further purified 150-fold by chromatography using thio-phosphorylated myosin light chain-agarose. MPPs-1, -2, and -3 were distinct from the major acid and alkaline phosphatases, and their activities were not affected by okadaic acid, microcystin-LR or Ca2+, and calmodulin, resembling the enzymatic properties of type 2C protein phosphatase of mammalian cells. The apparent molecular masses of MPPs-1, -2, and -3 on gel filtration were 53, 112, and 128 kDa, respectively. It was demonstrated that MPP-1 is a globular protein of 53-55 kDa and that MPPs-2 and -3 are oligomeric proteins that dissociate upon sucrose density gradient centrifugation, generating catalytic proteins of about 50 kDa. Since the substrate specificities of MPPs-1, -2, and -3 differed from each other both before and after sucrose density gradient centrifugation, it was suggested that the catalytic proteins of these three enzymes are distinct molecular species.
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PMID:Characterization of multiple molecular forms of Mg(2+)-dependent protein phosphatase from Saccharomyces cerevisiae. 808 94

Q10 values of the protein phosphatases that can dephosphorylate the regulatory light chain of smooth muscle myosin were determined. Six phosphatases were examined, i.e. skeletal muscle protein phosphatase 1c; protein phosphatase 2Ac; smooth muscle phosphatases (SMP) I, II, and IV; and myosin-associated protein phosphatase (MAP phosphatase). Among them, SMP-IV and MAP phosphatase, which can dephosphorylate intact smooth muscle myosin, showed extremely high Q10 values (5.3 and 5.2, respectively). On the other hand, the Q10 values of other tested phosphatases were within the range of the normal enzyme reaction (Q10 = 2.0). The rate of dephosphorylation of the myosin light chain in alpha-toxin-skinned strips was measured at different temperatures. The results provided a Q10 of 5.1, which was quite similar to those values obtained for SMP-IV and MAP phosphatase. These results suggest that the physiological myosin light chain phosphatases are SMP-IV and/or MAP phosphatase, i.e. type 1 protein phosphatases. The temperature dependence of maximum force, the steady-state extent of myosin light chain phosphorylation, and the relaxation rate of alpha-toxin-permeabilized rabbit portal vein smooth muscle strips were measured. Both maximum force and the extent of myosin light chain phosphorylation were significantly higher at lower temperature (15 degrees C) than at higher temperature (25 degrees C) under all pCa conditions tested, i.e. > 8, 6.3, and 5. The temperature dependence of the relaxation rate was much steeper (decreased 4 times by lowering the temperature from 25 to 15 degrees C) than that of the initial rate of increase in force development (decreased 1.4 times by lowering the temperature from 25 to 15 degrees C). These results are consistent with the Q10 values of myosin light chain phosphatases (Q10 = 5) and myosin light chain kinase (Q10 = 1.7) and further show that the smooth muscle type 1 phosphatases are responsible for the dephosphorylation of smooth muscle myosin in situ.
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PMID:Correlation between high temperature dependence of smooth muscle myosin light chain phosphatase activity and muscle relaxation rate. 811 26

The characteristics of actively growing smooth muscle cells (a variant, SM-3) were compared with those of growth-arrested cells with regard to response of myosin light chain (MLC) phosphorylation. Augmented MLC phosphorylation, in particular diphosphorylation, was observed in actively growing cells when stimulated with 30 microM prostaglandin F2alpha (PGF2alpha). The maximum level of diphosphorylation in growing cells was significantly higher than that in growth-arrested cells. The MLC diphosphorylation was sensitive to protein kinase C down-regulation by phorbol dibutylate and pretreatment by the protein kinase inhibitors, staurosporine (30 nM) and isoquinoline sulphonamide HA1077 (20 microM). The actively growing cells contained larger amounts of protein kinase C than growth-arrested cells. The phosphorylation sites of mono- and diphospho-MLC were determined to be MLC kinase-dependent sites (Thr18, Ser19). The PGF2alpha concentration/response curves of MLC diphosphorylation were shifted to the left and upwards in the presence of the protein phosphatase inhibitor calyculin A. These results suggest that PGF2alpha stimulation of actively growing SM-3 cells augments MLC kinase-dependent MLC diphosphorylation. Protein kinase C is involved indirectly in this reaction, possibly through MLC phosphatase-sensitive regulatory mechanisms.
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PMID:Myosin light chain diphosphorylation is enhanced by growth promotion of cultured smooth muscle cells. 866 62

A novel phosphorylation-dependent inhibitory protein (IP) of porcine aorta myosin light chain phosphatase (PA-MLCP) was purified to homogeneity from porcine aorta media. The molecular mass of IP was 20 kDa. IP phosphorylated by endogenous potentiating kinase (IP-K) inhibited not only PA-MLCP activity, but also that of the catalytic subunit of protein phosphatase-1. The amino acid sequence of a peptide derived from IP phosphorylated with IP-K, RHARVT*VK, shared one of the consensus sequences phosphorylatable by protein kinase C (PKC), where T* was phosphorylated. IP was phosphorylated by PKC and the phosphorylated product inhibited PA-MLCP as strongly as IP phosphorylated with IP-K.
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PMID:A novel protein phosphatase-1 inhibitory protein potentiated by protein kinase C. Isolation from porcine aorta media and characterization. 872 Jan 21

A variety of physical forces exist in a dynamic equilibrium in the vascular endothelium (EC) monolayer and serve to maintain EC responsiveness while preserving the integrity of the EC monolayer and barrier properties. Thrombin has potent effects on EC permeabilities disrupting the equilibrium between tethering forces (cadherins, focal adhesion plaque) and forces that increase centripetal tension primarily via myosin light chain (MLC) phosphorylation. Like other EC effects, thrombin-induced MLC kinase (MLCK) activation is dependent upon receptor proteolysis, Ca2+ mobilization, and activation of protein kinase C (PKC). While EC gap formation is central to barrier dysfunction and dependent upon activation of MLCK, (which phosphorylates MLC) an obligatory event in smooth muscle cell contraction, little is known regarding the events that reverse inflammatory responses, halt the contractile response, and initiate relaxation. However, as these events likely include MLC dephosphorylation, further examination of the processes that regulate MLC protein phosphatase activity, focal intercellular junctions, and extracellular matrix adhesions is needed. These investigations should yield new information as to how receptor occupancy is transduced into specific cellular responses, such as increased permeability, which promotes pathological vascular processes such as tissue edema formation and organ dysfunction.
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PMID:Regulation of thrombin-mediated endothelial cell contraction and permeability. 894 15

A myofibrillar form of smooth muscle myosin light chain phosphatase (MLCPase) was purified from turkey gizzard myofibrils, and it was found to be closely associated with the myosin light chain kinase (MLCKase). For this reason we have named this phosphatase the kinase- and myosin-associated protein phosphatase (KAMPPase). Subunits of the KAMPPase could be identified during the first ion exchange chromatography step. After further purification on calmodulin (CaM) and on thiophosphorylated regulatory myosin light chain affinity columns we obtained either a homogenous preparation of a 37-kDa catalytic (PC) subunit or a mixture of the PC subunit and variable amounts of a 67-kDa targeting (PT) subunit. The PT subunit bound the PC subunit to CaM affinity columns in a Ca2+-independent manner; thus, elution of the subunits required only high salt concentration. Specificity of interaction between these subunits was shown by the following observations: 1) activity of isolated PC subunit, but not of the PTC holoenzyme, was stimulated 10-20-fold after preincubation with 5-50 microM of CoCl2; 2) the pH activity profile of the PC subunit was modified by the PT subunit (the specific activity of the PTC holoenzyme was higher at neutral pH and lower at alkaline pH); and 3) affinity of the holoenzyme for unphosphorylated myosin was 3-fold higher, and for phosphorylated myosin it was 2-fold lower, in comparison with that of the purified PC subunit. KAMPPase was inhibited by okadaic acid (Ki = 250 nM), microcystin-LR (50 nM) and calyculin A (1.5 microM) but not by arachidonic acid or the heat-stable inhibitor (I-2), which suggested that this is a type PP1 or PP2A protein phosphatase.
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PMID:Purification and characterization of a kinase-associated, myofibrillar smooth muscle myosin light chain phosphatase possessing a calmodulin-targeting subunit. 905 93

We have previously demonstrated that agonists increase microvascular permeability through a phospholipase C-nitric oxide synthase-guanylate cyclase cascade. The aim of this study was to further investigate the downstream end of the signaling pathway with a focus on myosin light chain (MLC) phosphorylation. The apparent permeability coefficient to albumin was measured in isolated coronary venules. Under control conditions, the nitric oxide donor sodium nitroprusside, as well as the guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) activator 8-bromoguanosine 3',5'-cyclic monophosphate, increased venular permeability two- to threefold. Similarly, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate significantly elevated permeability. Inhibition of MLC phosphorylation with ML-7 significantly attenuated the hyperpermeability responses to the agonists. Furthermore, ML-7 dose dependently reduced basal venular permeability. Consistently, inhibition of dephosphorylation with the protein phosphatase inhibitor calyculin dramatically increased basal permeability. These results suggest that 1) PKG and PKC play an important signaling role in the regulation of endothelial barrier function and 2) MLC phosphorylation contributes to basal and agonist-stimulated microvascular permeability.
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PMID:Myosin light chain phosphorylation: modulation of basal and agonist-stimulated venular permeability. 908 22


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