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)

Members of the myogenic regulatory gene family, including MyoD, Myf5, Myogenin and MRF4, are specifically expressed in myoblast and skeletal muscle cells and play important roles in regulating skeletal muscle development and growth. They are capable of converting a variety of non-muscle cells into myoblasts and myotubes. To better understand their roles in the development of fish muscles, we have isolated the MyoD genomic genes from gilthead seabream (Sparus aurata), analyzed the genomic structures, patterns of expression and the regulation of muscle-specific expression. We have demonstrated that seabream contain two distinct non-allelic MyoDgenes, MyoD1 and MyoD2. Sequence analysis revealed that these two MyoD genes shared a similar gene structure. Expression studies demonstrated that they exhibited overlapping but distinct patterns of expression in seabream embryos and adult slow and fast muscles. MyoD1 was expressed in adaxial cells that give rise to slow muscles, and lateral somitic cells that give rise to fast muscles. Similarly, MyoD2 was initially expressed in both slow and fast muscle precursors. However, MyoD2 expression gradually disappeared in the adaxial cells of 10- to 15-somite-stage embryos, whereas its expression in fast muscle precursor cells was maintained. In adult skeletal muscles, MyoD1 was expressed in both slow and fast muscles, whereas MyoD2 was specifically expressed in fast muscles. Treating seabream embryos with forskolin, a protein kinase A activator, inhibited MyoD1 expression in adaxial cells, while expression in fast muscle precursors was not affected. Promoter analysis demonstrated that both MyoD1 and MyoD2 promoters could drive green fluorescence protein expression in muscle cells of zebrafish embryos. Together, these data suggest that the two non-allelic MyoD genes are functional in seabream and their expression is regulated differently in fast and slow muscles. Hedgehog signaling is required for induction of MyoDexpression in adaxial cells.
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PMID:Differential expression of two MyoD genes in fast and slow muscles of gilthead seabream ( Sparus aurata). 1207 Jun 11

Lasp-1 has been identified as a signaling molecule that is phosphorylated upon elevation of [cAMP]i in pancreas, intestine and gastric mucosa and is selectively expressed in cells within epithelial tissues. In the gastric parietal cell, cAMP-dependent phosphorylation induces the partial translocation of lasp-1 to the apically directed F-actin-rich canalicular membrane, which is the site of active HCl secretion. Lasp-1 is an unusual modular protein that contains an N-terminal LIM domain, a C-terminal SH3 domain and two internal nebulin repeats. Domain-based analyses have recently categorized this protein as an epithelial representative of the nebulin family, which also includes the actin binding, muscle-specific proteins, nebulin, nebulette and N-RAP. In this study, we show that lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. In addition, we provide evidence that lasp-1 is concentrated within focal complexes as well as in the leading edges of lamellipodia and the tips of filopodia in non-transformed gastric fibroblasts. In actin pull-down assays, the apparent K(d) of bacterially expressed his-tagged lasp-1 binding to F-actin was 2 micro M with a saturation stoichiometry of approximately 1:7. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the K(d) and decreased the B(max) for lasp-1 binding to F-actin. Microsequencing and site-directed mutagenesis localized the major in vivo and in vitro PKA-dependent phosphorylation sites in rabbit lasp-1 to S(99) and S(146). BLAST searches confirmed that both sites are conserved in human and chicken homologues. Transfection of lasp-1 cDNA encoding for alanine substitutions at S(99) and S(146), into parietal cells appeared to suppress the cAMP-dependent translocation of lasp-1 to the intracellular canalicular region. In gastric fibroblasts, exposure to the protein kinase C activator, PMA, was correlated with the translocation of lasp-1 into newly formed F-actin-rich lamellipodial extensions and nascent focal complexes. Since lasp-1 does not appear to be phosphorylated by PKC, these data suggest that other mechanisms in addition to cAMP-dependent phosphorylation can mediate the translocation of lasp-1 to regions of dynamic actin turnover. The localization of lasp-1 to these subcellular regions under a range of experimental conditions and the phosphorylation-dependent regulation of this protein in F-actin rich epithelial cells suggests an integral and possibly cell-specific role in modulating cytoskeletal/membrane-based cellular activities.
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PMID:Lasp-1 binds to non-muscle F-actin in vitro and is localized within multiple sites of dynamic actin assembly in vivo. 1243 67

LIM and SH3 domain protein (LASP-1) is a specific focal adhesion protein involved in cell migration. Overlay studies demonstrate that LASP-1 directly binds to the proline-rich domains of zyxin, lipoma preferred partner (LPP), and vasodilator-stimulated phosphoprotein (VASP), with zyxin being the most prominent interacting partner. Despite the LIM/zinc-finger domain, hypothesized to be involved in homodimerization, LASP-1 exists as a monomer. In vitro phosphorylation of recombinant mouse LASP-1 by cAMP- and cGMP-dependent protein kinase (PKA and PKG, respectively) occurs at serine 61, serine 99, and threonine 156 whereas in intact cells mouse LASP-1 is phosphorylated only at threonine 156. This site is different from the known in vivo phosphorylation sites in human (serine 146) and rabbit (serine 99 and serine 146). Nevertheless, immunofluorescence of LASP-1 in human and mouse mesangial cells revealed no difference in subcellular distribution. Exposure of the cells to forskolin induced a translocation of both, human and mouse LASP-1, from the focal contacts to the cell interior without affecting F-actin structure. Immunoblotting of LASP-1 in various mouse and human tissues detected a similar prominent expression in non-muscle tissue. Altogether, our data suggest so far no functional differences between human and mouse LASP-1.
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PMID:Phosphorylation of mouse LASP-1 on threonine 156 by cAMP- and cGMP-dependent protein kinase. 1546 19

Previous studies suggested that heavy chain phosphorylation regulates non-muscle myosin-II assembly in an isoform-specific manner, affecting the assembly of myosin-IIB, but not myosin-IIA. We re-examined the effects of heavy chain phosphorylation on myosin-IIA filament formation and also examined mts1 binding. We demonstrated that heavy chain phosphorylation by either protein kinase C (PKC) or casein kinase 2 (CK2) inhibits the assembly of myosin-IIA into filaments. PKC phosphorylation had no affect on mts1 binding, but CK2 phosphorylation decreased the affinity of mts1 for the myosin-IIA rod by approximately 6.5-fold. Mts1 destabilized PKC-phosphorylated myosin-IIA filaments and inhibited the assembly of myosin-IIA monomers with maximal inhibition of assembly and promotion of disassembly occurring at a molar ratio of one mts1 dimer per myosin-IIA rod. At this molar ratio, mts1 only weakly disassembled CK2-phosphorylated myosin-IIA filaments and weakly inhibited the assembly of CK2-phosphorylated myosin-IIA monomers. These observations demonstrate that CK2 phosphorylation of the myosin-IIA heavy chain protects against mts1-induced filament disassembly and inhibition of assembly, and suggest that heavy chain phosphorylation provides an additional level of regulation for the mts1-myosin-IIA interaction.
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PMID:Regulation of myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation. 1586 32

Two major physiological roles have been defined for zipper interacting protein kinase (ZIPK), regulation of apoptosis in non-muscle cells and regulation of Ca(2+) sensitization in smooth muscle. Although much attention has focused on the role of ZIPK in the regulation of apoptotic events, its roles in smooth muscle are likely to have equal if not greater physiological relevance. We first identified ZIPK as a major protein kinase controlling the phosphorylation of myosin phosphatase (SMPP-1M) and the inhibitor protein CPI17 in smooth muscle. Phosphorylation of SMPP-1M and CPI17 by ZIPK inhibits phosphatase activity towards myosin and causes profound Ca(2+) sensitization and contraction in smooth muscle. ZIPK will also directly phosphorylate both muscle and non-muscle myosin. The highly selective actions of ZIPK in the control of myosin phosphorylation potentially make the enzyme an ideal candidate for the development of novel therapeutics to treat smooth muscle related disorders such as hypertension or asthma.
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PMID:ZIP kinase, a key regulator of myosin protein phosphatase 1. 1600 10

Phosphoinositide 3-kinase (PI(3)K) is a unique enzyme characterized by both lipid and protein kinase activities. Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. Notably, knocking down endogenous tropomyosin expression using siRNAs that target different regions if tropomyosin resulted in complete inhibition of betaAR endocytosis, showing that non-muscle tropomyosin is essential for agonist-mediated receptor internalization. These studies demonstrate a previously unknown role for the protein phosphorylation activity of PI(3)K in betaAR internalization and identify non-muscle tropomyosin as a cellular substrate for protein kinase activity of PI(3)K.
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PMID:Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. 1605 69

Disruption of protein synthesis and folding results in ER stress, which is associated with the pathophysiology of diverse diseases affecting secretory and muscle cells. Cells are protected against ER stress by activation of the unfolded protein response (UPR) that is regulated by the protein kinase PERK, which phosphorylates the translation initiation factor 2 eIF2alpha to attenuate protein synthesis. PERK-/- cells are unable to modulate ER protein load and experience high levels of ER stress. In addition to its role in protein synthesis, the ER also orchestrates many signaling events essential for cell survival, prominent among which is Ca2+ signaling. It is not known, however, whether there is a relationship between ER stress and the function of the Ca2+-signaling pathway in muscle and non-muscle cells. To directly address this question we characterized Ca2+ signaling in the secretory pancreatic and parotid acinar cells and in urinary bladder smooth muscle (UBSM) cells obtained from PERK-/- and wild-type mice. Deletion of PERK that results in high levels of ER stress, and distention and fragmentation of the ER slowed the rate of agonist-mediated Ca2+ release from the ER and reduced Ca2+-induced Ca2+ release, although IP3 production, localization of the IP3 receptors, IP3-mediated Ca2+ release, Ca(v)1.2 current and RyRs activity remained unaltered. On the other hand, ER stress disrupted the integrity of the Ca2+-signaling complexes in both secretory and UBSM cells, as revealed by markedly reduced co-immunoprecipitation of plasma membrane- and ER-resident Ca2+-signaling proteins. These findings establish a relationship between the unfolding protein response, ER stress and Ca2+ signaling and highlight the importance of communication within the terminal ER-plasma membrane microdomain for propagation of the Ca2+ signal from the plasma membrane into the cell.
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PMID:ER stress disrupts Ca2+-signaling complexes and Ca2+ regulation in secretory and muscle cells from PERK-knockout mice. 1635 59

Contraction forces generated by non-muscle cells such as fibroblasts play important roles in determining cell morphology, vasoconstriction, and/or wound healing. However, few factors that induce cell contraction forces are known, such as lysophosphatidic acid and thrombin. Our study analyzed various plant extracts for ingredients that induce generation of cell contraction forces in fibroblasts populating collagen gels. We found that an extract of Horse chestnut (Aesculus hippocastanum) is able to induce such contraction forces in fibroblasts. The involvement of actin polymerization and stress fiber formation in the force generation was suggested by inhibition of this effect by cytochalasin D and by Rhodamine phalloidin. Rho kinase inhibitors (Y27632 and HA1077) and a Rho inhibitor (exoenzyme C3) significantly inhibited the force generation induced by the Horse chestnut extract. H7, which inhibits Rho kinase as well as other protein kinases, also significantly inhibited induction of force generation. However, inhibitors of other protein kinases such as myosin light chain kinase (ML-9), protein kinase C (Calphostin), protein kinase A (KT5720), and tyrosine kinase (Genistein, Herbimycin A) had no effect on force generation induced by Horse chestnut extract. These results suggest that the Horse chestnut extract induces generation of contraction forces in fibroblasts through stress fiber formation followed by activation of Rho protein and Rho kinase but not myosin light chain kinase or other protein kinases.
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PMID:Horse chestnut extract induces contraction force generation in fibroblasts through activation of Rho/Rho kinase. 1675 96

The dystrophin-related and -associated protein dystrobrevin is a component of the dystrophin-associated protein complex, which directly links the cytoskeleton to the extracellular matrix. It is now thought that this complex also serves as a dynamic scaffold for signaling proteins, and dystrobrevin may play a role in this context. Since dystrobrevin involvement in signaling pathways seems to be dependent on its interaction with other proteins, we sought new insights and performed a two-hybrid screen of a mouse brain cDNA library using beta-dystrobrevin, the isoform expressed in non-muscle tissues, as bait. Among the positive clones characterized after the screen, one encodes the regulatory subunit RIalpha of the cAMP-dependent protein kinase A (PKA). We confirmed the interaction by in vitro and in vivo association assays, and mapped the binding site of beta-dystrobrevin on RIalpha to the amino-terminal region encompassing the dimerization/docking domain of PKA regulatory subunit. We also found that the domain of interaction for RIalpha is contained in the amino-terminal region of beta-dystrobrevin. We obtained evidence that beta-dystrobrevin also interacts directly with RIIbeta, and that not only beta-dystrobrevin but also alpha-dystrobrevin interacts with PKA regulatory subunits. We show that both alpha and beta-dystrobrevin are specific phosphorylation substrates for PKA and that protein phosphatase 2A (PP2A) is associated with dystrobrevins. Our results suggest a new role for dystrobrevin as a scaffold protein that may play a role in different cellular processes involving PKA signaling.
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PMID:Association of dystrobrevin and regulatory subunit of protein kinase A: a new role for dystrobrevin as a scaffold for signaling proteins. 1761 Aug 95

The novel myelin-associated glycoprotein (MAG) inhibitor BENZ binds to the N-acetylneuraminic acid (Neu5Ac) portion of the N-terminal Ig-like domain of MAG. Treatment of rat dorsal root ganglion (DRG) cell cultures with BENZ-induced outgrowth of neurofilament 200-positive neurites improved survival of neurons and increased the number of GFAP-positive cells, as determined by fluorescence and confocal laser microscopy and by Western immunoblotting. Furthermore, treatment of DRG cell cultures with BENZ repressed gene and protein expression of the small GTPase RhoA but induced expression of Rho GTP-activating proteins 5 and 24, likely to counteract protein kinase A activity. Specifically, expression of inhibitors of neurite outgrowth, for example, Rock2 and PAK4, was repressed, but cofilin 1, a promoter of axonal growth, was induced. We propose that the MAG inhibitor BENZ abrogates the RhoA-ROCK-cofilin pathway to promote neurite outgrowth. Our findings require confirmation by in vivo animal studies.
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PMID:The myelin-associated glycoprotein inhibitor BENZ induces outgrowth and survival of rat dorsal root ganglion cell cultures. 1772 62


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