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)

Phosphoinositide kinases play central roles in signal transduction by phosphorylating the inositol ring at specific positions. The structure of one such enzyme, type IIbeta phosphatidylinositol phosphate kinase, reveals a protein kinase ATP-binding core and demonstrates that all phosphoinositide kinases belong to one superfamily. The enzyme is a disc-shaped homodimer with a 33 x 48 A basic flat face that suggests an electrostatic mechanism for plasma membrane targeting. Conserved basic residues form a putative phosphatidylinositol phosphate specificity site. The substrate-binding site is open on one side, consistent with dual specificity for phosphatidylinositol 3- and 5-phosphates. A modeled complex with membrane-bound substrate and ATP shows how a phosphoinositide kinase can phosphorylate its substrate in situ at the membrane interface.
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PMID:Structure of type IIbeta phosphatidylinositol phosphate kinase: a protein kinase fold flattened for interfacial phosphorylation. 975 29

The high-affinity nerve growth factor receptor (gp140TrkA) is a tyrosine kinase receptor. The dimeric ligand, nerve growth factor, activates the receptor by stabilizing homodimer formation, which initiates transautophosphorylation. Suramin is a symmetrical planar polyanionic molecule which is being used as a novel experimental anti-neoplastic agent. Proposed mechanisms of the drug's anti-proliferative activity include blocking mitogenic stimulatory growth factors or inhibition of tumor-specific cellular enzymes. In PC12 cells and in dorsal root ganglion neurons, suramin has been shown to act as a partial agonist for gp140TrkA. We now demonstrate direct activation of gp140TrkA by suramin using in vitro protein kinase assays and receptor dimerization studies. Additionally, activation of phosphatidylinositol-3-kinase by suramin and nerve growth factor was observed with 10-min exposure. The addition of anti-nerve growth factor antibodies along with suramin did not reduce the level of gp140TrkA phosphorylation, excluding induction of an autocrine loop of nerve growth factor release and activation. This demonstrates that a small polyanion can directly activate gp140TrkA via receptor dimerization. Our study reveals a suramin-induced homodimerization of gp140TrkA. This finding correlated with significant neurite outgrowth in naive PC12 cells exposed to the drug. Studies will be initiated to design structural analogs of suramin which possess neurotrophic properties with no associated neurotoxicity.
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PMID:Direct activation of the high-affinity nerve growth factor receptor by a non-peptide symmetrical polyanion. 975 73

Stage-specific activator protein (SSAP) is a 41-kDa polypeptide that binds to embryonic enhancer elements of the sea urchin late H1 gene. These enhancer elements mediate the transcriptional activation of the late H1 gene in a temporally specific manner at the mid-blastula stage of embryogenesis. Although SSAP can transactivate the late H1 gene only at late stages of the development, it resides in the sea urchin nucleus and maintains DNA binding activity throughout early embryogenesis. In addition, it has been shown that SSAP undergoes a conversion from a 41-kDa monomer to a approximately 80- to 100-kDa dimer when the late H1 gene is activated. We have demonstrated that SSAP is differentially phosphorylated during embryogenesis. Serine 87, a cyclic AMP-dependent protein kinase consensus site located in the N-terminal DNA binding domain, is constitutively phosphorylated. At the mid-blastula stage of embryogenesis, temporally correlated with SSAP dimer formation and late H1 gene activation, a threonine residue in the C-terminal transactivation domain is phosphorylated. This phosphorylation can be catalyzed by a break-ended double-stranded DNA-activated protein kinase activity from the sea urchin nucleus in vitro. Microinjection of synthetic SSAP mRNAs encoding either serine or threonine phosphorylation mutants results in the failure to transactivate reporter genes that contain the enhancer element, suggesting that both serine and threonine phosphorylation of SSAP are required for the activation of the late H1 gene. Furthermore, SSAP can undergo blastula-stage-specific homodimerization through its GQ-rich transactivation domain. The late-specific threonine phosphorylation in this domain is essential for the dimer assembly. These observations indicate that temporally regulated SSAP activation is promoted by threonine phosphorylation on its transactivation domain, which triggers the formation of a transcriptionally active SSAP homodimer.
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PMID:Temporal activation of the sea urchin late H1 gene requires stage-specific phosphorylation of the embryonic transcription factor SSAP. 1020 92

The mechanisms of nitric oxide (NO)-mediated inhibition of vascular smooth muscle (VSM) cell proliferation are still obscure. Cyclins A and E in association with cyclin-dependent kinase 2 (cdk2) serve as positive regulators for mammalian cell cycle progression through the G1/S checkpoint of the cell cycle and subsequent cell proliferation. Therefore, we have tested the effect of adenovirus-mediated transfection of the endothelial nitric oxide synthase (eNOS) gene into guinea pig coronary VSM cells on platelet-derived growth factor (BB homodimer) (PDGF-BB)-stimulated cell proliferation and the expression of cell cycle regulatory molecules. Transfection of the eNOS gene (eNOS) into VSM cells significantly inhibited (P < 0.05) [3H]thymidine incorporation into the DNA in response to PDGF-BB stimulation compared with lacZ-transfected control cells. The eNOS transfer significantly inhibited (P < 0.05) PDGF-BB-induced proliferating cell nuclear antigen (PCNA) and cyclin A expression in VSM cells compared with cells transfected with the control vector. The time course of cyclin E expression in response to PDGF-BB stimulation was delayed in eNOS-transfected cells. Levels of cyclin-dependent kinase inhibitors p21 and p27 were not significantly affected by eNOS transfer. eNOS transfer did not decrease PDGF-beta receptor number, affinity, and autophosphorylation measured by radioreceptor assay and Western analysis. These results suggest that inhibition of PDGF-stimulated expression of cyclin A, cyclin E, and PCNA is the target of NO action. These findings could explain, at least in part, NO-mediated inhibition of VSM cell proliferation.
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PMID:NOS gene transfer inhibits expression of cell cycle regulatory molecules in vascular smooth muscle cells. 1033 Feb 27

Activins were originally isolated based on their ability to stimulate follicle-stimulating hormone secretion but later they have been shown to regulate a number of different cellular functions such as nerve cell survival, mesoderm induction during early embryogenesis as well as hematopoiesis. We studied the regulation of activin A, a homodimer of betaA-subunits, mRNA and protein in K562 erythroleukemia cells, which are known to be induced toward the erythroid lineage in response to activin or TGF-beta or toward the megakaryocytic lineage by the phorbol ester protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA). Here we show by Northern blot analysis as well as by Western and ligand blotting that TPA strongly promotes activin betaA-subunit mRNA and activin A protein expression in K562 cells in time- and concentration dependent manner. In contrast, neither activin A nor TGF-beta induced betaA-subunit mRNA expression during erythroid differentiation in K562 cells. Interestingly, whereas activin type II receptors are not regulated during K562 cell differentiation (Hilden et al. (1994) Blood 83, 2163-2170), we now show that the activin type I and IB receptor mRNAs are clearly induced by TPA but not by activin or TGF-beta. We also show that the inducing effect of TPA on expression of activin betaA-subunit mRNA is potentiated by the protein kinase A activator 8-bromo-cAMP. We conclude that activin A and its type I receptors appear to be co-ordinately up-regulated during megakaryocytic differentiation of K562 cells.
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PMID:Co-ordinate expression of activin A and its type I receptor mRNAs during phorbol ester-induced differentiation of human K562 erythroleukemia cells. 1045 61

Hepatocyte growth factor (HGF) regulates a wide variety of biological activities by binding to the tyrosine kinase receptor Met. In HGF-treated hepatocarcinoma cells, we observed a biphasic activation of AP-1 and AP-2 transcription factors. For NF-kappaB complex the p50-p50 homodimer was activated before the p50-p65 heterodimer, and c-Myc/Max DNA-binding activity increased thereafter. Since these transcription factors are responders to mitogenic stimulation through protein kinase transducers, we tested the effects of inhibitors of these enzymes on the DNA binding after HGF treatment. Inhibition of protein kinase C (PKC) with H7 strikingly activated NF-kappaB above the values observed after HGF alone. Under this inhibitory condition, Met tyrosine phosphorylation was elevated as though the phosphorylation-dependent activity of the receptor was partially blocked by activation of PKC due to HGF. NF-kappaB DNA binding seems to be related to Met triggering by HGF since it was largely prevented by genistein treatment, which blocks receptor activity. Phosphatidylinositol 3-kinase seems to be involved in AP-1 binding activity stimulated by HGF. It is noteworthy that Met is responsive to HGF stimulating postreceptor signaling, which converges on the activation of transcription factors acting coordinately to regulate target gene expression.
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PMID:Hepatocyte growth factor signal coupling to various transcription factors depends on triggering of Met receptor and protein kinase transducers in human hepatoma cells HepG2. 1073 74

Activin A (a homodimer of two activin betaA subunits) has been shown to induce the neuronal differentiation of rat pheochromocytoma PC12 cells. We studied activin A and its receptor gene expression in human pheochromocytomas in vivo and in vitro to clarify the potential involvement of activin A in the pathophysiology of these tumors. We first screened 20 pheochromocytomas and nine normal adrenal tissues for activin betaA mRNA expression. Northern blots hybridized with specific oligonucleotide probes detected weak signals for activin betaA transcripts in pheochromocytomas. Both type I and type II activin receptor (ActR-I, ActR-IB and ActR-II) mRNA expression was also detectable in the pheochromocytoma tissues. In primary cultures of pheochromocytoma cells, expression of activin betaA mRNA was readily detectable by Northern blotting, and secretion of activin A into the conditioned medium was confirmed by an enzyme-linked immunosorbent assay. The expression of activin betaA mRNA and secretion of activin A were induced by (Bu)(2)cAMP after 1 and 3 days of treatment (all P<0.05). A protein kinase inhibitor, staurosporine, inhibited the basal and (Bu)(2)cAMP-induced accumulation of activin betaA mRNA (P<0.05). In addition, induction of chromaffin phenotype by dexamethasone also inhibited the basal and (Bu)(2)cAMP-induced expression of activin A at both mRNA and protein levels (all P<0.05). In contrast, the expression of ActR-I and ActR-IB mRNAs was not affected by these agents in cultured pheochromocytoma cells. In summary, activin betaA subunit and activin receptors are expressed in human pheochromocytomas. Production of activin A in cultured pheochromocytoma cells is induced through the protein kinase A pathway, but reduced during chromaffin differentiation. Therefore, activin A may function as a local neurotrophic factor via an auto/paracrine manner in human pheochromocytomas.
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PMID:Expression of activin A and its receptors in human pheochromocytomas. 1081 Mar 14

X-ray crystal structures of the NF-kappa B.I kappa B alpha complex revealed an extensive and complex protein-protein interface involving independent structural elements present in both I kappa B alpha and NF-kappa B. In this study, we employ a gel electrophoretic mobility shift assay to assess and quantitate the relative contributions of the observed interactions toward overall complex binding affinity. I kappa B alpha preferentially binds to the p50/p65 heterodimer and p65 homodimer, with binding to p50 homodimer being significantly weaker. Our results indicate that the nuclear localization sequence and the region C-terminal to it of the NF-kappa B p65 subunit is a major contributor to NF-kappa B. I kappa B alpha complex formation. Additionally, there are no contacts between the corresponding nuclear localization signal tetrapeptide of p50 and I kappa B alpha. A second set of interactions involving the acidic C-terminal/PEST-like region of I kappa B alpha and the NF-kappa B p65 subunit N-terminal domain also contributes binding energy toward formation of the complex. This interaction is highly dynamic and nonspecific in nature, as shown by oxidative cysteine cross-linking. Phosphorylation of the C-terminal/PEST-like region by casein kinase II further enhances binding.
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PMID:Mechanism of I kappa B alpha binding to NF-kappa B dimers. 1088 38

The unfolded protein response (UPR) is a signal transduction pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). In Saccharomyces cerevisiae the ER transmembrane receptor, Ire1p, transmits the signal to the nucleus culminating in the transcriptional activation of genes encoding an adaptive response. Yeast Ire1p requires both protein kinase and site-specific endoribonuclease (RNase) activities to signal the UPR. In mammalian cells, two homologs, Ire1 alpha and Ire1 beta, are implicated in signaling the UPR. To elucidate the RNase requirement for mammalian Ire1 function, we have identified five amino acid residues within IRE1 alpha that are essential for RNase activity but not kinase activity. These mutants were used to demonstrate that the RNase activity is required for UPR activation by IRE1 alpha and IRE1 beta. In addition, the data support that IRE1 RNase is activated by dimerization-induced trans-autophosphorylation and requires a homodimer of catalytically functional RNase domains. Finally, the RNase activity of wild-type IRE1 alpha down-regulates hIre1 alpha mRNA expression by a novel mechanism involving cis-mediated IRE1 alpha-dependent cleavage at three specific sites within the 5' end of Ire1 alpha mRNA.
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PMID:The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. 1106 89

The transcription factor c-Maf has been suggested to regulate the activity of gamma-crystallin promoters in lens fibre cells. We here show that the transactivation potential of c-Maf and MafB for the rat gammaD-crystallin Maf-responsive element (gammaD MARE) is dependent upon the cellular context and, using chimeric and single domain mutants, that c-Maf is most likely to be the cognate factor for the gammaD MARE in the lens. Transactivation of the gammaD MARE by c-Maf in lens cells was not enhanced by c-Fos or c-Jun and was not blocked by dominant negative c-Fos or c-Jun constructs. c-Maf can activate the gammaD MARE as a homodimer since activation of the gammaD-crystallin promoter in P19 embryonic carcinoma cells required only c-Maf, but none of a number of c-Fos and c-Jun family members tested. Transactivation by c-Maf was inhibited by activation of protein kinase A (PKA) (by signal transduction agonist forskolin) or of protein kinase C (PKC) (by signal transduction agonist tetradecanoyl phorbol acetate). Site-directed mutagenesis showed that this effect is not mediated by phosphorylation of the consensus PKA/PKC site in the extended DNA-binding domain, but likely involves activation of MAP kinase kinase, as inhibition by PD98059 increased transactivation by c-Maf.
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PMID:c-Maf, the gammaD-crystallin Maf-responsive element and growth factor regulation. 1184 9


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