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)

Two novel cAMP response element binding protein (CREB) splice variants were found by reverse transcription-polymerase chain reaction cloning by using mouse brain RNA as a template. One splice variant, named Delta-14, lacks 14 nucleotides at the beginning of exon 9 of the CREBDelta isoform. The other, named Delta-35, lacks 35 nucleotides at the beginning of exon 8 of CREBDelta. These nucleotide deletions cause frame shifts for codon usage, producing proteins which conserve the major phosphorylation site (Ser(133)) but lack the basic/leucine zipper domain, which is essential for binding to DNA and to other transcription factors. Both variants are widely expressed in peripheral tissues, but are enriched in brain, thymus, and testis. CREBDelta-14 and Delta-35 variant proteins were expressed by using an in vitro translation system and by transfecting into human embryonic kidney 293 cells. Both variants were detected by a CREB antibody that recognizes the CREBDelta amino terminus, but not by an antibody which recognizes the CREBDelta carboxy terminus, as would be predicted based on the frame shift. Activation of the cAMP pathway increased phospho-CREB immunoreactivity, indicating that these variants are substrates of cAMP-dependent protein kinase. In addition, immunocytochemical analysis demonstrated that CREBDelta-14 and Delta-35 are primarily cytosolic, whereas CREBalpha is predominantly in the nucleus. Finally, expression of CREBDelta-14 or Delta-35 decreased cAMP responsive element-chloramphenicol acetyltransferase reporter activity, demonstrating that both can function as repressors of endogenous CREB.
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PMID:Identification and functional analysis of novel cAMP response element binding protein splice variants lacking the basic/leucine zipper domain. 1053 95

Contraction and relaxation of smooth muscle are regulated by myosin light-chain kinase and myosin phosphatase through phosphorylation and dephosphorylation of myosin light chains. Cyclic guanosine monophosphate (cGMP)-dependent protein kinase Ialpha (cGKIalpha) mediates physiologic relaxation of vascular smooth muscle in response to nitric oxide and cGMP. It is shown here that cGKIalpha is targeted to the smooth muscle cell contractile apparatus by a leucine zipper interaction with the myosin-binding subunit (MBS) of myosin phosphatase. Uncoupling of the cGKIalpha-MBS interaction prevents cGMP-dependent dephosphorylation of myosin light chain, demonstrating that this interaction is essential to the regulation of vascular smooth muscle cell tone.
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PMID:Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha. 1056 69

cGMP-dependent protein kinase (cGK) is a major intracellular receptor of cGMP and is implicated in several signal transduction pathways. To identify proteins that participate in the cGMP/cGK signaling pathway, we employed the yeast two-hybrid system with cGK Ialpha as bait. cDNAs encoding slow skeletal troponin T (skTnT) were isolated from both mouse embryo and human skeletal muscle cDNA libraries. The skTnT protein interacted with cGK Ibeta but not with cGK II nor cAMP-dependent protein kinase. The yeast two-hybrid and in vitro binding assays revealed that the N-terminal region of cGK Ialpha, containing the leucine zipper motif, is sufficient for the association with skTnT. In vivo analysis, mutations in cGK Ialpha, which disrupted the leucine zipper motif, were shown to completely abolish the binding to skTnT. Furthermore, cGK I also interacted with cardiac TnT (cTnT) but not with cardiac troponin I (cTnI). Together with the observations that cTnI is a good substrate for cGK I and is effectively phosphorylated in the presence of cTnT in vitro, these findings suggest that TnT functions as an anchoring protein for cGK I and that cGK I may participate in the regulation of muscle contraction through phosphorylation of TnI.
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PMID:A novel interaction of cGMP-dependent protein kinase I with troponin T. 1060 15

Prostate apoptosis response-4 (Par-4) is a 38-kDa protein initially identified as the product of a gene upregulated in prostate tumor cells undergoing apoptosis. Par-4 contains both a death domain and a leucine zipper domain, and has been shown to interact with several proteins known to modulate apoptosis, including protein kinase Czeta, Bcl-2, and caspase-8. A rapid increase in Par-4 levels occurs in neurons undergoing apoptosis in a variety of paradigms, including trophic factor withdrawal, and exposure to oxidative and metabolic insults. Par-4, which can be induced at the translational level, acts at an early stage of the apoptotic cascade prior to caspase activation and mitochondrial dysfunction. The mechanism whereby Par-4 promotes apoptosis may involve inhibition of the antiapoptotic transcription factor NF-kappaB and suppression of Bcl-2 expression and/or function. Studies of postmortem tissues from patients and animal models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS), and HIV encephalitis, have documented increased levels of Par-4 in vulnerable neurons. Manipulations that block Par-4 expression or function prevent neuronal cell death in models of each disorder, suggesting a critical role for Par-4 in the neurodegenerative process. Interestingly, Par-4 levels rapidly increase in synaptic terminals following various insults, and such local increases in Par-4 levels appear to play important roles in synaptic dysfunction and degeneration. A better understanding of the molecular and cellular biology of Par-4 will help clarify mechanisms of neuronal apoptosis, and may lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.
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PMID:Par-4: an emerging pivotal player in neuronal apoptosis and neurodegenerative disorders. 1069 Dec 89

Recently, cyclic GMP-dependent protein kinase (cGK) was shown to translocate to the nucleus and regulate gene transcription. To determine whether cGK I proteins function as transcriptional activators, we produced the constructs of cGK Ialpha or Ibeta fused with the DNA binding domain of the yeast transcriptional activator GAL4. Here, we demonstrate that the amino-terminal region of cGK Ibeta (amino acids 1-107) exhibits transcriptional activation in yeast. However, full-length cGK Ialpha and Ibeta and the amino-terminal region of cGK Ialpha had no transcriptional activation function. Amino acid replacement in the leucine zipper motif of the amino-terminal region of cGK Ibeta substantially reduced transcriptional activation. These results suggest that the Ibeta-specific region in cGK I proteins may interact with other proteins by way of the leucine zipper motif and has a transcriptional activation function.
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PMID:Specific domain of cGMP-dependent protein kinase Ibeta but not Ialpha functions as a transcriptional activator in yeast. 1077 36

Using human glycogen synthase kinase 3beta (GSK-3beta) as bait in the yeast two-hybrid system, we identified a novel human centrosome associated protein, hNinein. When the full length cDNA of hNinein was sequenced, it showed that an open reading frame encoded a protein consisting of 2047 amino acids with a predicted molecular mass of 239 kDa. The features of this protein include a potential GTP binding site, a large coiled-coil domain together with four leucine zipper domains and a GSK-3beta binding site. Fluorescence microscopy experiment showed that hNinein is localized in the pericentriolar matrix of the centrosome. In addition, hNinein also showed to react with centrosomal autoantibody sera. Our findings suggest that hNinein may be involved in the formation of centrosome matrix and interacts with the GSK-3beta, implying that it may also be regulated by GSK-3beta phosphorylation signaling.
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PMID:Cloning and characterization of a novel human ninein protein that interacts with the glycogen synthase kinase 3beta. 1100 22

The induction of the dehydration-responsive Arabidopsis gene, rd29B, is mediated mainly by abscisic acid (ABA). Promoter analysis of rd29B indicated that two ABA-responsive elements (ABREs) are required for the dehydration-responsive expression of rd29B as cis-acting elements. Three cDNAs encoding basic leucine zipper (bZIP)-type ABRE-binding proteins were isolated by using the yeast one-hybrid system and were designated AREB1, AREB2, and AREB3 (ABA-responsive element binding protein). Transcription of the AREB1 and AREB2 genes is up-regulated by drought, NaCl, and ABA treatment in vegetative tissues. In a transient transactivation experiment using Arabidopsis leaf protoplasts, both the AREB1 and AREB2 proteins activated transcription of a reporter gene driven by ABRE. AREB1 and AREB2 required ABA for their activation, because their transactivation activities were repressed in aba2 and abi1 mutants and enhanced in an era1 mutant. Activation of AREBs by ABA was suppressed by protein kinase inhibitors. These results suggest that both AREB1 and AREB2 function as transcriptional activators in the ABA-inducible expression of rd29B, and further that ABA-dependent posttranscriptional activation of AREB1 and AREB2, probably by phosphorylation, is necessary for their maximum activation by ABA. Using cultured Arabidopsis cells, we demonstrated that a specific ABA-activated protein kinase of 42-kDa phosphorylated conserved N-terminal regions in the AREB proteins.
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PMID:Arabidopsis basic leucine zipper transcription factors involved in an abscisic acid-dependent signal transduction pathway under drought and high-salinity conditions. 1100 31

Cyclic AMP-response element modulator alpha (CREMalpha) is a transcription factor that is highly related to cAMP-response element-binding protein (CREB) but represses cAMP-induced gene expression from simple artificial promoters containing a cAMP-response element (CRE). CREMalpha lacks two glutamine-rich Q regions that, in CREB, are thought to be necessary for transcriptional activation. Nevertheless, protein kinase A stimulation induces CREMalpha to activate the complex native promoter in the phosphoenolpyruvate carboxykinase (PEPCK) gene. To study this phenomenon in the absence of protein kinase A stimulation, we introduced a mutation into CREMalpha to allow constitutive binding to the coactivator CREB-binding protein. This mutant, CREMalpha(DIEDML), constitutively activated the PEPCK promoter. By engineering the leucine zipper regions of CREMalpha(DIEDML) and CREB(DIEDML) to direct their patterns of dimerization, we found that only CREMalpha(DIEDML) homodimers fully activated the PEPCK promoter. By using a series of deletion and block mutants of the PEPCK promoter, we found that activation by CREMalpha(DIEDML) depended on the CRE and two CCAAT/enhancer-binding protein (C/EBP) sites. A dominant negative inhibitor of C/EBP, A-C/EBP, suppressed activation by CREMalpha(DIEDML). Furthermore, a GAL4-C/EBPalpha fusion protein and CREMalpha(DIEDML) cooperatively activated a promoter containing three GAL4 sites and the PEPCK CRE. Thus, we propose that the C/EBP sites in the PEPCK promoter allow CREMalpha to activate transcription despite its lack of Q regions.
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PMID:Cooperative mechanism of transcriptional activation by a cyclic AMP-response element modulator alpha mutant containing a motif for constitutive binding to CREB-binding protein. 1109 86

The mixed lineage kinase (MLK) family is a recently described protein kinase family. The MLKs contain a kinase domain followed by a dual leucine zipper-like motif. We previously reported the molecular cloning of LZK (leucine zipper-bearing kinase), a novel MLK, and that LZK activated the c-Jun NH2 terminal kinase (JNK)/stress-activated protein kinase (SAPK) pathway through MKK7 in cells. Here, we reveal that LZK forms dimers/oligomers through its dual leucine zipper-like motif, and that this is necessary for activation of the JNK/SAPK pathway. We also identify the C-terminal functional region of LZK, which is indispensable for the activation of SEK1, but not that of MKK7.
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PMID:Identification and characterization of functional domains in a mixed lineage kinase LZK. 1116 70

We report here the molecular cloning and characterization of human haspin cDNA and its genomic DNA construct. The haspin protein is a unique protein kinase, first isolated from mouse testis. Specifically expressed in mouse testicular germ cells, haspin is suggested to play a role in cell cycle arrest in haploid spermatids. Detection of human haspin by Northern blot analysis showed that the major transcript was 2.8 kilobases long and detected exclusively in the testis. The entire coding region of the human cDNA showed 68% identity with mouse haspin. The predicted amino acid sequence showed strong conservation of the kinase catalytic domain, leucine zipper, potential phosphorylation sites, and MEF2B homologous region, but a relatively unique N:-terminal region. Human haspin protein was also demonstrated to have protein kinase activity. The human haspin gene was mapped to chromosome 17p13 by computer database cloning of human genomic DNA. Furthermore, the genomic structure of human haspin was proven to be intronless and the whole transcription unit was found to be located in an intron of the integrin alphaE2 gene.
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PMID:Cloning and characterization of human haspin gene encoding haploid germ cell-specific nuclear protein kinase. 1122 40


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