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 homogenate of MC3T3-E1 cells hydrolysed phosphotyrosine, but not phosphoserine or phosphothreonine at acidic pH. It dephosphorylated lysozyme and Raytide (a gastrin analogue peptide) phosphorylated by tyrosine kinase, but showed little activity toward histones phosphorylated by cyclic AMP-dependent protein kinase. Dephosphorylation of phosphorylated lysozyme and Raytide were inhibited by zinc and vanadate, but were insensitive to okadaic acid. These data suggest that the osteoblastic cell line MC3T3-E1 has a phosphotyrosyl protein phosphatase-like activity that may participate in cellular regulation involving protein tyrosine phosphorylation.
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PMID:Phosphotyrosyl protein phosphatase-like activity of a clonal osteoblastic cell line (MC3T3-E1 cell). 865 86

Classical and novel protein kinase C (PKC) isozymes contain two, so-called cysteine-rich zinc finger domains that represent the binding sites for phorbol esters and the diacylglycerols. X-ray crystallographic, mutational, and modeling studies are providing detailed understanding of the interactions between the phorbol esters and individual PKC zinc fingers. In the present study, we explore the roles of the individual zinc fingers in the context of the intact enzyme. Our approach was to mutate either the first, the second, or both zinc fingers of PKCdelta, to express the mutated enzyme in NIH 3T3 cells, and to monitor the effect of the mutations on the dose-response curve for translocation induced by phorbol 12-myristate 13-acetate. The introduced mutations change into glycine the consensus proline in the phorbol ester binding loop of the zinc finger; in the isolated zinc finger, this mutation causes a 125-fold decrease in phorbol ester binding affinity. We observed that mutation in the first zinc finger caused almost no shift in the dose-response curve for translocation; mutation in the second zinc finger caused a 21-fold shift, whereas mutation in both zinc fingers caused a 138-fold shift. We conclude that the zinc fingers in the intact PKC are not equivalent and that the second zinc finger plays the predominant role in translocation of protein kinase Cdelta in response to phorbol 12-myristate 13-acetate. Our findings have important implications for the understanding and design of PKC inhibitors targeted to the zinc finger domains.
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PMID:Non-equivalent roles for the first and second zinc fingers of protein kinase Cdelta. Effect of their mutation on phorbol ester-induced translocation in NIH 3T3 cells. 870 64

The tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of proteins interact with and transduce signals for members of the TNF receptor superfamily. TRAF1, TRAF2, and TRAF3 share a conserved C-terminal TRAF domain. TRAF2 plays a key role in transducing signals for activation of the transcription factor nuclear factor-kappaB (NF-kappaB). We have performed extensive mutational analysis on TRAF2, examining the requirements for NF-kappaB activation, self-association, and interaction with other molecules involved in TNF signaling. Examination of point mutants and TRAF2-TRAF3 chimeric proteins indicates that the N-terminal RING finger and two adjacent zinc fingers of TRAF2 are required for NF-kappaB activation. The two distinct TRAF-N and TRAF-C subdomains of the TRAF domain appear to independently mediate self-association and interaction with TRAF1. Interaction of TRAF2 with TNF-R2 and TRADD requires sequences at the C terminus of the TRAF-C domain, whereas interaction with the protein kinase receptor-interacting protein V(RIP) occurs via sequences at the N terminus of the TRAF-C domain. Thus, distinct domains of TRAF2 are involved in recruitment and signaling functions.
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PMID:Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins. 870 8

Protein phosphorylation induced by neurotransmitters, hormones, different growth factors, nerve impulse is involved in the regulation of a wide variety of physiological processes in the nervous system. The data on abnormal phosphorylation/dephosphorylation processes in the brain of patients with Alzheimer's disease are considered. In AD there are a few phosphoproteins with known function, protein kinases, phosphatases that are altered. The own data on the decrease in casein kinase 2 activity, content and altered spectrum of substrate proteins in Alzheimer's disease are presented. Drastic reductions in zinc- and magnesium-stimulated protein tyrosine activities are also recorded. The important role of abnormalities in the phosphorylation/dephosphorylation system in the stimulation of pathological processes in Alzheimer's disease is noted.
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PMID:[Protein phosphorylation in the normal nervous system and in Alzheimer's disease]. 875 73

The sequential transcriptional activation of cyclins, the regulatory subunits of cell cycle specific kinases, regulates progress through the cell cycle. In mitogen-stimulated cells cyclin D1 induction in early G1 is followed by induction of cyclin E, activation of the cyclin-dependent kinase Cdk2, and hyperphosphorylation of the retinoblastoma gene product (pRB) in mid-to-late G1 phase. T-47D breast cancer cells expressing cyclin D1 under the control of a metal-responsive metallothionein promoter were used to determine whether Cdk2 activation and pRB hyperphosphorylation are consequences of cyclin D1 induction. A 4-5-fold increase in cyclin D1 protein abundance was followed by approximately 2-fold increases in cyclin E protein abundance and Cdk2 activity and by hyperphosphorylation of pRB. These responses were apparent approximately 3 h after the increase in cyclin D1 protein, and approximately 3 h prior to the entry of cyclin D1-stimulated cells into S phase 12 h after zinc treatment. Cyclin D1 immunoprecipitates contained Cdk4 but no detectable Cdk2 and displayed pRb but not histone H1 kinase activity. Cdk2 activation was therefore likely to be due to increased abundance of cyclin E/Cdk2 complexes rather than formation of active cyclin D1/Cdk2 complexes. The sequence of events following zinc induction of cyclin D1 thus mimicked that following mitogen induction of cyclin D1. These data show that cyclin D1 induction is sufficient for Cdk2 activation and pRB hyperphosphorylation in T-47D human breast cancer cells, providing evidence that cyclin D1 induction is a critical event in G1 phase progression.
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PMID:Inducible expression of cyclin D1 in T-47D human breast cancer cells is sufficient for Cdk2 activation and pRB hyperphosphorylation. 886 12

Using insertional mutagenesis, we have isolated a "stalky" mutant in which cells destined to become spores end up as stalk cells. Similar mutants were previously observed after chemical mutagenesis, but the affected gene could not be isolated. Our mutant, like the previous ones, is in stkA. Its defect is cell-autonomous and not overcome by overexpressing cAMP-dependent protein kinase. stkA is strongly expressed in the prespore region of aggregates but not in the anterior prestalk zone. The mutant expresses normal levels of prespore-cell transcripts but fails to produce the spore transcript spiA. stkA encodes a predicted 99 kDa protein (STKA) with two putative C4 zinc fingers, one of which is a GATA-type finger, indicating that it may be a transcription factor. This conclusion is supported by localization of STKA in the nucleus.
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PMID:Identification of the cell fate gene stalky in Dictyostelium. 889

Three-dimensional models of the five functional modules in human protein kinase C alpha (PKC alpha) have been generated on the basis of known related structures. The catalytic region at the C-terminus of the sequence and the N-terminal auto-inhibitory pseudo-substrate have been modeled using the crystal structure complex of cAMP-dependent protein kinase (cAPK) and PKI peptide. While the N-terminal helix of the catalytic region of PKC alpha is predicted to be in a different location compared with cAPK, the C-terminal extension is modeled like that in the cAPK. The predicted permissive phosphorylation site of PKC alpha, Thr 497, is found to be entirely consistent with the mutagenesis studies. Basic Lys and Arg residues in the pseudo-substrate make several specific interactions with acidic residues in the catalytic region and may interact with the permissive phosphorylation site. Models of the two zinc-binding modules of PKC alpha are based on nuclear magnetic resonance and crystal structures of such modules in other PKC isoforms while the calcium phospholipid binding module (C2) is based on the crystal structure of a repeating unit in synaptotagmin I. Phorbol ester binding regions in zinc-binding modules and the calcium binding region in the C2 domain are similar to those in the basis structures. A hypothetical model of the relative positions of all five modules has the putative lipid binding ends of the C2 and the two zinc-binding domains pointing in the same direction and may serve as a basis for further experiments.
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PMID:Structural aspects of the functional modules in human protein kinase-C alpha deduced from comparative analyses. 891 29

The carboxy-terminal cytoplasmic regions of the rat neurokinin 1 (substance P) and neurokinin 2 (neurokinin A) receptors have been exchanged to determine if this region of the neurokinin 1 receptor is involved in its desensitization. When expressed at similar levels in stably transfected Chinese hamster ovary (CHO) cell lines, receptors containing the carboxy-terminal region of the neurokinin 1 receptor desensitized significantly more (as measured by reduction of the inositol 1,4,5-trisphosphate response) when preexposed for 1 min to 1 microM neurokinin, indicating a role for the carboxy-terminal region of the neurokinin 1 receptor in its desensitization. Measurement of receptor internalization using radiolabeled neurokinins (0.3 nM) indicated that approximately 75-80% of the receptors were internalized in each cell line after 10 min at 37 degrees C, with no observable correlation between neurokinin receptor desensitization and internalization. Measurement of loss of receptor surface sites for cell lines CHO NK1 and CHO NK1NK2 following exposure to 1 microM substance P also indicated no obvious relationship between the percent desensitization and percent of receptors internalized. Also, two inhibitors of neurokinin 1 receptor internalization, phenylarsine oxide and hyperosmolar sucrose, did not inhibit neurokinin 1 receptor desensitization. The protein kinase inhibitors Ro 31-8220, staurosporine, and Zn2+ had no effect on neurokinin 1 receptor desensitization, indicating that the kinases affected by these agents are not rate-limiting in neurokinin 1 receptor desensitization in this system.
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PMID:Desensitization of the neurokinin 1 receptor is mediated by the receptor carboxy-terminal region, but is not caused by receptor internalization. 893 68

Adenosine 3' 5'-monophosphate (cyclic AMP) - dependent protein kinase was purified about 42 fold from the M. smegmatis by ammonium sulphate fractionation followed by DEAE-cellulose and phosphocellulose column chromatography. SDS-PAGE revealed two prominent bands, with molecular masses of 55 KDa and 58 KDa. The enzyme preferentially utilized phosvitin and Histones as exogenous phosphate acceptor. Mg2+ ions were essential for enzyme activity, other metal ions like Ca2+, Zn2+, Co2+ and Mn2+, could not substitute for Mg2+. Inhibition of enzyme activity by thiol reagents, 5-5'-dithio bis (2-nitrobenzoic acid) and N-ethylmaleimide suggest that the cystein residues in the protein kinase might be located at or near the active site of the enzyme.
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PMID:Partial purification and characterization of cyclic adenosine monophosphate dependent protein kinase from mycobacterium smegmatis. 893 28

Dystrophin is a protein product of the gene responsible for Duchenne and Becker muscular dystrophy. The protein is localized to the inner surface of sarcolemma and is associated with a group of membrane (glyco)proteins. Dystrophin links cytoskeletal actins via the dystrophin-associated protein complex to extracellular matrix protein, laminin. This structural organization implicates the role of dystrophin in stabilizing the sarcolemma of muscle fibers. Precisely how dystrophin functions is far from clear. The presence of an array of isoforms of the C-terminal region of dystrophin suggests that dystrophin may have functions other than structural. In agreement, many potential phosphorylation sites are found in the C-terminal region of dystrophin, and the C-terminal region of dystrophin is phosphorylated both in vitro and in vivo by many protein kinases, including MAP kinase, p34cdc2 kinase, CaM kinase, and casein kinase, and is dephosphorylated by calcineurin. The C-terminal domain of dystrophin is also a substrate for hierarchical phosphorylation by casein kinase-2 and GSK-3. These observations, in accordance with the finding that the cysteine-rich region binds to Ca2+, Zn2+, and calmodulin, suggest an active involvement of dystrophin in transducing signals across muscle sarcolemma. Phosphorylation-dephosphorylation of the C-terminal region of dystrophin may play a role in regulating dystrophin-protein interactions and (or) transducing signal from the extracellular matrix via the dystrophin molecule to the cytoskeleton.
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PMID:Phosphorylation of the carboxyl-terminal region of dystrophin. 896 Mar 49


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