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)

Stimulation of aortic smooth muscle cells with platelet-derived growth factor BB homodimer (PDGF-BB) leads to the rapid activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MAPKK). Compounds that increase cAMP and activate protein kinase A (PKA)--prostaglandin E2, isoproterenol, cholera toxin, and forskolin--were found to inhibit the PDGF-BB-induced activation of MAPKK and MAPK. Forskolin, but not the inactive analogue 1,9-dideoxyforskolin, inhibited PDGF-BB-stimulated MAPKK and MAPK activation in a dose-dependent manner. PKA antagonism of MAPK signaling was observed at all doses of PDGF-BB or PDGF-AA. PKA did not inhibit MAPKK and MAPK activity in vitro, and MAPKK and MAPK from extracts of forskolin-treated cells could be activated normally with purified Raf-1 and MAPKK, respectively, suggesting that PKA blocked signaling upstream of MAPKK. Neither PDGF-BB-stimulated tyrosine autophosphorylation of the PDGF receptor beta subunit nor inositol monophosphate accumulation was affected by increased PKA activity, suggesting that PKA inhibits events downstream of the PDGF receptor. This study provides an example of cross talk between two important signaling systems activated by physiological stimuli in smooth muscle cells--namely, the PKA pathway and the growth factor-activated MAPK cascade.
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PMID:Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. 769 89

Guanylyl cyclase-A (GC-A), a receptor for A-type natriuretic peptide (ANP), contains an extracellular ligand-binding domain, a single transmembrane domain, and intracellular protein kinase-like and cyclase catalytic domains. Expression of the putative cyclase catalytic region (HCAT) resulted in the formation of an active enzyme that migrated as a homodimer on gel filtration columns; treatment with sodium trichloroacetate caused dissociation of the dimer and a loss of cyclase activity. Co-transfection of HCAT and full-length GC-A led to elevated basal intact cell cGMP concentrations and increased cell homogenate guanylyl cyclase activity. However, atrial natriuretic peptide-induced elevations of cGMP and cyclase activity were inhibited by the introduction of HCAT. Alanine scanning mutagenesis of highly conserved residues within HCAT identified one mutation (D893A) that destroyed enzyme activity but not the ability of the mutant subunit to form homodimers. The mutant subunit inhibited the cyclase activity of wild-type HCAT (approximately 70%) as well as that of full-length GC-A (approximately 85%) in co-expression studies where the amount of wild-type HCAT or full-length GC-A was not altered. Unlike co-transfection with wild-type HCAT, co-transfection of HCA-TD893A and GC-A did not result in elevated basal intact cell cGMP concentrations. For the first time we describe deletion and point mutations within the plasma membrane family of guanylyl cyclase receptors that result in the formation of effective dominant negative proteins.
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PMID:Dominant negative mutations of the guanylyl cyclase-A receptor. Extracellular domain deletion and catalytic domain point mutations. 781 5

Id is a helix-loop-helix protein which forms heterodimer with ubiquitous and/or tissue-specific basic helix-loop-helix proteins and inhibits their DNA binding. It has been noted that putative phosphorylation sites for various protein kinases exist in rat Id1, Id2 and Id3. We show here that Id1 and Id2 can be phosphorylated in vitro by cAMP-dependent protein kinase, Id2 and Id3 by cdc2 kinase, and all three Ids by protein kinase C. The phosphorylated Id1 was actually immunoprecipitated in nerve-growth-factor-stimulated PC12 cells. Gel mobility shift assays, however, demonstrated that neither phosphorylation of Id proteins by cAMP-dependent protein kinase nor phosphorylation of E47 by protein kinase C affected the inhibition of E47 homodimer formation and its DNA binding. Taken together with other observations, phosphorylation of Id proteins may play a role in regulation of cell differentiation but not directly in the dimerization and DNA binding.
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PMID:Phosphorylation of helix-loop-helix proteins ID1, ID2 and ID3. 786 97

We have characterized regulation of type-1 plasminogen activator inhibitor (PAI-1) gene expression by phorbol 12-myristate 13-acetate (PMA) and the cAMP-inducing agent forskolin in the human breast carcinoma cell line MCF-7. PMA caused a strong induction of PAI-1, while forskolin suppressed the PMA response. Transfection experiments with fusion genes showed that sequences mediating PMA induction as well as forskolin suppression were present between base pairs -100 and -30 of the 5'-flanking region of the PAI-1 gene. The region was found to contain two Sp1 binding sites. A proximal sequence in the region, TGAGTTCA (P box), with sequence similarity to phorbol ester response elements (TRE) as well as to cAMP response elements (CRE), bound a low-abundance, as yet unidentified nuclear protein in MCF-7 cells. This sequence had a higher affinity to purified c-jun homodimer than to c-jun/c-fos heterodimer in MCF-7 nuclear extracts; it had no affinity to the proteins binding to CRE consensus sequences in these extracts. A distal TRE-like sequence, TGAGTGG (D box), had a weak affinity to c-jun/c-fos heterodimer and c-jun homodimer; binding of proteins to this sequence was facilitated by binding of proteins to the P box. Both the P box and the D box were necessary for PMA responsiveness, suggesting a cooperativity between the two binding sites. A mutation of the P box removing the CRE similarity abolished the forskolin suppression of the PMA response. We propose that the protein kinase C and the protein kinase A signal-transduction pathways, with opposite effects on PAI-1 gene expression converge by modulating differently P-box-binding proteins.
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PMID:A common response element mediates differential effects of phorbol esters and forskolin on type-1 plasminogen activator inhibitor gene expression in human breast carcinoma cells. 811 99

Activating transcription factor-3 (ATF-3) is one member of a large family of leucine zipper transcription factors which bind to promoters responsive to cAMP and phorbol ester at the related cAMP (CRE) and phorbol ester response elements. We report here that ATF-3 is coexpressed with the neuropeptide precursor proenkephalin in human neuroblastoma SK-N-MC cells. Cotransfection experiments indicate that activation of proenkephalin gene expression by ATF-3 is dependent upon both the catalytic subunit of the cAMP-dependent protein kinase and the CRE-2 element. The CRE-2 element is essential for second messenger-inducible expression and is known to bind AP-1-like transcription factors. ATF-3 expressed in bacteria or from rabbit reticulocyte lysates binds to the proenkephalin CRE-2 element as a homodimer and as a heterodimer with Jun-D, another activator of proenkephalin transcription. ATF-3 stimulates binding of Jun-D to the proenkephalin CRE-2 element and acts synergistically with Jun-D to induce proenkephalin gene expression. Sequential immunoprecipitations of ATF-3 from SK-N-MC cells expressing proenkephalin indicate that ATF-3 is complexed with Jun-D in vivo and that both proteins are highly phosphorylated. Together, our results suggest that ATF-3 may play an important role in the regulation of gene expression by cAMP-dependent intracellular signaling pathways.
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PMID:Activating transcription factor-3 stimulates 3',5'-cyclic adenosine monophosphate-dependent gene expression. 815 31

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse fibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-receptors results in receptor dimerization and subsequent activation of tyrosine kinase activity in the cytoplasmic protein domain, autophosphorylation of the receptor being the first event in the transduction cascade. Before the ligand-receptor complex is internalized and degraded, receptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphorylation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentration of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited by the PDGF-receptor association are phosphatidylinositol-3'-kinase, ras-GTPase-activating protein, phospholipase C-gamma, serine-threonine kinase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear factors such as c-fos and c-myc genes and dephosphorylation of c-jun occurs, V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studied as a model system for the autocrine stimulation of the PDGF receptor.
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PMID:Platelet derived growth factor/tyrosine kinase receptor mediated proliferation. 822 Jan 10

The histidine protein kinase CheA plays an essential role in stimulus-response coupling during bacterial chemotaxis. The kinase is a homodimer that catalyzes the reversible transfer of a gamma-phosphoryl group from ATP to the N-3 position of one of its own histidine residues. Kinetic studies of rates of autophosphorylation show a second order dependence on CheA concentrations at submicromolar levels that is consistent with dissociation of the homodimer into inactive monomers. The dissociation was confirmed by chemical cross-linking studies. The dissociation constant (CheA2<==>2CheA; KD = 0.2-0.4 microM) was not affected by nucleotide binding, histidine phosphorylation, or binding of the response regulator, CheY. The turnover number per active site within a dimer (assuming 2 independent sites/dimer) at saturating ATP was approximately 10/min. The kinetics of autophosphorylation and ATP/ADP exchange indicated that the dissociation constants of ATP and ADP bound to CheA were similar (KD values approximately 0.2-0.3 mM), whereas ATP had a reduced affinity for CheA approximately P (KD approximately 0.8 mM) compared with ADP (KD approximately 0.3 mM). The rates of phosphotransfer from bound ATP to the phosphoaccepting histidine and from the phosphohistidine back to ADP seem to be essentially equal (kcat approximately 10 min-1).
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PMID:Dimerization is required for the activity of the protein histidine kinase CheA that mediates signal transduction in bacterial chemotaxis. 855 8

The myogenic regulatory factors (MRFs) are a subclass of a much larger group of basic helix-loop-helix transcription factors which includes members of the E protein such as E47, E2-2, and HEB. Although the MRFs are unique in their ability to confer a myogenic phenotype on nonmuscle cells, they require E protein partners to form a MRF-E protein heterodimer, which represents the functional myogenesis-inducing complex. The mechanisms controlling homodimer and heterodimer formation in vivo remain largely unknown, although it is likely that posttranslational modification of one or both basic helix-loop-helix partners is critical to this regulatory event. In this respect, MyoD and MRF4, both members of the MRF family, exist in vivo as phosphoproteins and contains multiple consensus phosphorylation sites, including sites for casein kinase II (CKII) phosphorylation. In this study, we demonstrate that overexpression of CKII increases the transcriptional activities of MRF4 and MyoD in vivo. Interestingly, mutation of the individual CKII sites within MRF4 and MyoF does not alter the ability of CKII to enhance MRF transcriptional activity, suggesting that the effect of CKII expression on the MRFs is indirect. Given that the MRFs require dimerization with E protein partners to activate muscle-specific transcription, the effects of CKII expression on E protein function also were examined. Our studies show that E47 serves as an in vitro substrate for CKII and that CKII-phosphorylated E-47 proteins no longer bind to DNA. These observations were confirmed by in vivo experiments showing that overexpressing of CKII produces a dramatic reduction in E47 homodimer-directed transcription. We conclude from these studies that CKII may act as a positive regulator of myogenesis by preventing E protein homodimers from binding to muscle gene regulatory elements.
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PMID:Casein kinase II increases the transcriptional activities of MRF4 and MyoD independently of their direct phosphorylation. 865 35

Signal transduction across cell membranes often involves interactions among identical receptor subunits, but the contribution of individual subunits is not well understood. The chemoreceptors of enteric bacteria mediate attractant responses by interrupting a phosphotransfer circuit initiated at receptor complexes with the protein kinase CheA. The aspartate receptor (Tar) is a homodimer, and oligomerized cytoplasmic domains stimulate CheA activity much more than monomers do in vitro. Intragenic complementation was used to show in Escherichia coli that heterodimers containing one full-length and one truncated Tar subunit mediated responses to aspartate in the presence of full-length Tar homodimers that could not bind aspartate. Thus, a Tar dimer containing only one cytoplasmic domain can initiate an attractant (inhibitory) signal, although it may not be able to stimulate kinase activity of CheA.
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PMID:Attractant signaling by an aspartate chemoreceptor dimer with a single cytoplasmic domain. 892 93

Granulosa cell-derived inhibin A (a dimer of alpha- and beta A-subunits), activin A (a homodimer of beta A-subunits) and the activin-binding protein follistatin are important regulators of human ovarian steroidogenesis. We here studied how 8-bromo-cAMP (8br-cAMP), a protein kinase A activator, and 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C activator, affect the steady-state levels of alpha- and beta A-subunit and follistatin mRNAs in cultured human granulosa-luteal cells. 8br-cAMP induced alpha- and beta A-subunit and follistatin steady-state mRNA levels in a time- and concentration-dependent manner. The levels of alpha-subunit mRNAs were stimulated by 8br-cAMP in a sustained manner with a maximal induction seen at the time points 24 and 48 h. By contrast, beta A-subunit and follistatin mRNA levels were rapidly and transiently induced by 8br-cAMP with maximal effects observed at 3 h and 8 h, respectively. TPA did not affect basal alpha-subunit mRNA levels but it rapidly induced beta A-subunit mRNAs at 3 h and the stimulation was still evident at 48 h. TPA induced follistatin mRNA levels with kinetics similar to 8br-cAMP but to a lesser extent. Moreover, 8br-cAMP and TPA stimulated beta A-subunit and follistatin mRNA levels synergistically at 3 h. By contrast, TPA had a potent inhibitory effect on 8br-cAMP- and hCG-induced alpha-subunit levels. Neither 8br-cAMP nor TPA regulated inhibin/activin beta B-subunit mRNA levels. Taken together the activation of protein kinase-A and -C by 8br-cAMP and TPA, respectively, lead to clearly differential responses in the steady-state levels of inhibin activin alpha- and beta A-subunit and follistatin mRNAs. These results suggest that the inhibin A vs. activin A ratio as well as follistatin levels are regulated by multiple second-messenger pathways in the human ovary.
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PMID:Differential regulation of inhibin/activin alpha- and beta A-subunit and follistin mRNAs by cyclic AMP and phorbol ester in cultured human granulosa-luteal cells. 886 60


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