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)

To screen the compounds that inhibit protein kinases, we used an assay system in which activities of protein kinase A, protein kinase C, src family protein tyrosine kinases and eukaryotic elongation factor 2 kinase were simultaneously detected on a single gel for the cytoplasmic protein kinases. For the receptor type protein kinases, EGFR and Flt-1 tyrosine kinases were examined. Here, we briefly described some of the protein kinase inhibitors that have been approved or are under clinical development, and present some novel inhibitors that were found in our screening system.
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PMID:[Screening of protein kinase inhibitors]. 1511 88

Dishevelled (Dvl) is a cytoplasmic protein involved in the Wnt-Frizzled signaling cascade, which has also been shown to interact with the cytoskeleton in part through inhibition of glycogen synthase kinase 3beta (GSK3beta). Using mouse neuroblastoma 2A (N2A) cells as a model system, we have found that overexpression of Dvl promotes the outgrowth of neurite-like processes, and leads to the induction of a striking, bipolar morphologic phenotype during neuronal differentiation. In contrast, suppression of Dvl expression using isoform-specific siRNAs led to an inhibition of neurite outgrowth in these cells. In order to further elucidate the mechanism(s) responsible for this effect, we overexpressed several mutant forms of Dvl in the N2A cells, including deletions in each of the three major functional subdomains of the protein (DeltaDIX, DeltaPDZ, DeltaDEP) and point mutations in the two well-defined interaction motifs within the DIX domain (the actin-binding and vesicle-association elements; K58A and K68A/E69A, respectively). These experiments revealed that the DIX domain (and its vesicle-binding subregion) was essential for Dvl's effect on neurite extension and morphogenesis in N2A cells. In contrast, direct overexpression of a degradation-resistant form of beta-catenin (S37A), or a dominant negative GSK3beta mutant (K85R), had no effect on neurite outgrowth or morphology in neuronally differentiating N2A cells; exposure of cells to a pharmacologic inhibitor of GSK3beta (lithium) also had no effect. Taken together, these results suggest that Dvl induces cytoskeletal and morphologic rearrangements in neuronal differentiating N2A cells through a mechanism that cannot be attributed exclusively to modulation of GSK3beta or beta-catenin activity, but which does depend upon a DIX-domain/vesicle-association-dependent signaling pathway.
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PMID:Dishevelled promotes neurite outgrowth in neuronal differentiating neuroblastoma 2A cells, via a DIX-domain dependent pathway. 1554 27

We describe an unusual hybrid histidine protein kinase, which is important for spatially coupling cell aggregation and sporulation during fruiting body formation in Myxococcus xanthus. A rodK mutant makes abnormal fruiting bodies and spores develop outside the fruiting bodies. RodK is a soluble, cytoplasmic protein, which contains an N-terminal sensor domain, a histidine protein kinase domain and three receiver domains. In vitro phosphorylation assays showed that RodK possesses kinase activity. Kinase activity is essential for RodK function in vivo. RodK is present in vegetative cells and remains present until the late aggregation stage, after which the level decreases in a manner that depends on the intercellular A-signal. Genetic evidence suggests that RodK may regulate multiple temporally separated events during fruiting body formation including stimulation of early developmental gene expression, inhibition of A-signal production and inhibition of the intercellular C-signal transduction pathway. We speculate that RodK undergoes a change in activity during development, which is reflected in changes in phosphotransfer to the receiver domains.
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PMID:Coupling of multicellular morphogenesis and cellular differentiation by an unusual hybrid histidine protein kinase in Myxococcus xanthus. 1588 26

Myeloproliferative disorders (MPD) represent a subcategory of hematological malignancies and are characterized by a stem cell-derived clonal proliferation of myeloid cells including erythrocytes, platelets, and leucocytes. Traditionally, the term 'MPD' included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). At present, these four disorders are referred to as 'classic' MPD and are distinguished from a spectrum of other MPD-like clinicopathologic entities that are operationally classified as 'atypical' MPD. The oncogenic mutations(s) in classic MPD are unknown except for CML, which is associated with an activating mutation (Bcr/Abl) of the gene encoding for the Abl cytoplasmic protein kinase (PTK). In the last 3 months, a somatic point mutation of JAK2 (JAK2(V617F)), the gene encoding for another cytoplasmic PTK was reported in the majority of patients with PV and approximately half of those with either ET or MMM. The same mutation was also found in a small number of patients with either atypical MPD or the myelodysplastic syndrome but not in normal controls, germline tissue including T lymphocytes, and patients with secondary erythrocytosis. In vitro, JAK2(V617F) was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell lines. In vivo, murine bone marrow transduced with a retrovirus containing JAK2(V617F) induced erythrocytosis in the transplanted mice. Taken together, these observations suggest that JAK2(V617F) is an acquired myeloid lineage-specific mutation that engenders a pathogenetic relevance for the PV phenotype in MPD.
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PMID:JAK2 in myeloproliferative disorders is not just another kinase. 1597 Jul 5

The adenomatous polyposis coli (Apc) gene is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. The Apc gene product (APC), basically a cytoplasmic protein, blocks cell cycle progression and plays crucial roles in development. The APC binds to beta-catenin, axin and glycogen synthase kinase 3beta to form a large protein complex, in which beta-catenin is phosphorylated and broken down, resulting in negative regulation of the Wnt signaling pathway. Most of the mutated Apc genes in colorectal tumors lack beta-catenin-binding regions and fail to inhibit Wnt signaling, leading to overproliferation of tumor cells. The APC, having some nuclear localizing signals in its molecule, can also be localized in the nucleus. The nuclear APC exports excess beta-catenin to the cytoplasm. Through its C-terminus, APC binds to post-synaptic density discs large zonula occludens domain-containing proteins, such as discs large (DLG) and post-synaptic density (PSD)-95, and may play important roles in epithelial morphogenesis, brain development and neuronal functions. In addition, APC is involved in cell motility through its association with microtubules and APC-stimulated guanine nucleotide exchange factor. Colocalization of APC and DLG is dependent on microtubules. The Apc gene is highly expressed in the embryonic and postnatal developing brain. Recently, we found that APC is required for the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by facilitating the clustering of PSD-95 and these receptors at the postsynapse. In addition, APC is present in astrocytes, although its role in astrocytes is, as yet, unknown.
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PMID:Adenomatous polyposis coli (Apc) tumor suppressor gene as a multifunctional gene. 1615 75

C(4) phosphoenolpyruvate carboxylase (PEPC) is post-translationally regulated by reversible phosphorylation of a specific N-terminal seryl residue in response to light/dark transitions of the parent leaf tissue. The protein-serine kinase (PEPC-PK) that phosphorylates/activates this mesophyll-cytoplasm target enzyme is slowly, but strikingly, activated by high light and inactivated in darkness in vivo by a mechanism involving cytoplasmic protein synthesis/degradation as a primary component. In this report, evidence is presented indicating that the inhibition of Calvin cycle activity by a variety of mesophyll (3-(3,4-dichlorophenyl)-1,1-dimethylurea, isocil, methyl viologen) and bundle sheath (dl-glyceraldehyde)-directed photosynthesis inhibitors blocks the light activation of maize (Zea mays L.) PEPC-PK and the ensuing regulatory phosphorylation of its target enzyme in vivo. Based on these and related observations, we propose that the Calvin cycle supplies the C(4) mesophyll cell with (a) a putative signal (e.g. phosphorylated metabolite, amino acid) that interacts with the cytoplasmic protein synthesis event to effect the light activation of PEPC-PK and the concomitant phosphorylation of PEPC, and (b) high levels of known positive effectors (e.g. triose-phosphate, glucose-6-phosphate) that interact directly with the carboxylase. The combined result of this complex regulatory cascade is to effectively desensitize PEPC to feedback inhibition by the millimolar levels of l-malate required for rapid diffusive transport to the bundle sheath during high rates of C(4) photosynthesis.
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PMID:Light activation of maize phosphoenolpyruvate carboxylase protein-serine kinase activity is inhibited by mesophyll and bundle sheath-directed photosynthesis inhibitors. 1666 6

In mammalian cells, cytoplasmic protein aggregates generally coalesce to form aggresomal particles. Recent studies indicate that prion-infected cells produce prion protein (PrP) aggresomes, and that such aggregates may be present in the brain of infected mice. The molecular activity of PrP aggresomes has not been fully investigated. We report that PrP aggresomes initiate a cell stress response by activating the RNA-dependent protein kinase (PKR). Activated PKR phosphorylates the translation initiation factor eIF2alpha, resulting in protein synthesis shut-off. However, other components of the stress response, including the assembly of poly(A)+ RNA-containing stress granules and the synthesis of heat shock protein 70, are repressed. In situ hybridization experiments and affinity chromatography on oligo(dT)-cellulose showed that PrP aggresomes bind poly(A)+ RNA, and are therefore poly(A)+ ribonucleoprotein complexes. These findings support a model in which PrP aggresomes send neuronal cells into untimely demise by modifying the cell stress response, and by inducing the aggregation of poly(A)+ RNA.
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PMID:Prion protein aggresomes are poly(A)+ ribonucleoprotein complexes that induce a PKR-mediated deficient cell stress response. 1802 89

Many flowering plants possess systems of self-incompatibility (SI) to prevent inbreeding. In Brassica, SI recognition is controlled by the multiallelic gene complex (S-haplotypes) at the S-locus, which encodes both the male determinant S-locus protein 11 (SP11/SCR) and the female determinant S-receptor kinase (SRK). Upon self-pollination, the S-haplotype-specific interaction between the pollen-borne SP11 and the cognate stigmatic SRK receptor induces SI signaling in the stigmatic papilla cell and results in rejection of the self-pollen. Our genetic analysis of a self-compatible mutant revealed the involvement of a cytoplasmic protein kinase, M-locus protein kinase (MLPK), in the SI signaling, but its exact physiological function remains unknown. In this study, we identified two different MLPK transcripts, MLPKf1 and MLPKf2, which are produced using alternative transcriptional initiation sites and encode two isoforms that differ only at the N termini. While MLPKf1 and MLPKf2 exhibited distinct expression profiles, both were expressed in papilla cells. MLPKf1 localizes to the plasma membrane through its N-terminal myristoylation motif, while MLPKf2 localizes to the plasma membrane through its N-terminal hydrophobic region. Although both MLPKf1 and MLPKf2 could independently complement the mlpk/mlpk mutation, their mutant forms that lack the plasma membrane localization motifs failed to complement the mutation. Furthermore, a bimolecular fluorescence complementation assay revealed direct interactions between SRK and the MLPK isoforms in planta. These results suggest that MLPK isoforms localize to the papilla cell membrane and interact directly with SRK to transduce SI signaling.
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PMID:Two distinct forms of M-locus protein kinase localize to the plasma membrane and interact directly with S-locus receptor kinase to transduce self-incompatibility signaling in Brassica rapa. 1806 92

Osmotic stress is one of the severest environmental pressures for plants, commonly occurring under natural growing condition due to drought, salinity, cold and wounding. Plants sensitively respond to these stresses by activating a set of genes, which encode proteins necessary to overcome the crises. We screened such genes from tobacco plants, and identified a particular clone, which encoded a 45 kDa protein kinase belonging to the plant receptor-like cytoplasmic protein kinase class-VII, NAK (novel Arabidopsis protein kinase) group. The clone was consequently designated as NtNAK (Nicotiana tabacum NAK, accession number: DQ447159). GFP-NtNAK fusion protein was localized in both cytoplasm and nucleus, and bacterially expressed NtNAK exhibited in vitro kinase activity. Its transcripts were clearly induced upon treatments of leaves with salt, mannitol, low temperature and also with abscisic and jasmonic acids and ethylene. These properties indicated NtNAK to be a typical osmo-stress-responsive protein kinase. Its target protein(s) were then screened by the yeast two-hybrid system, and one clone encoding a 32 kDa protein was identified. The protein resembled a potato stress-responsive protein CK251806, and designated as NtCK25 (accession number: DQ448851). Bacterially expressed NtCK25 was phosphorylated by NtNAK, and NtCK25-GFP fusion protein was exclusively localized in nucleus. The structure of NtCK25 was found to be similar to a human nuclear body protein, SP110, which is involved in DNA/protein binding regulation. This suggested that, perceiving osmo-stress signal, NtNAK phosphorylates and activates NtCK25, which might function in regulation of nucleus function. The present study thus suggests that NtNAK/NtCK25 constitutes a novel phosphorylation pathway for osmotic-stress response in plants.
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PMID:A novel protein phosphorylation pathway involved in osmotic-stress response in tobacco plants. 1934 Sep 23

Protein Kinase-Like Non-kinases (PKLNKs), which are closely related to protein kinases, lack the crucial catalytic aspartate in the catalytic loop, and hence cannot function as protein kinase, have been analysed. Using various sensitive sequence analysis methods, we have recognized 82 PKLNKs from four higher eukaryotic organisms, namely, Homo sapiens, Mus musculus, Rattus norvegicus, and Drosophila melanogaster. On the basis of their domain combination and function, PKLNKs have been classified mainly into four categories: (1) Ligand binding PKLNKs, (2) PKLNKs with extracellular protein-protein interaction domain, (3) PKLNKs involved in dimerization, and (4) PKLNKs with cytoplasmic protein-protein interaction module. While members of the first two classes of PKLNKs have transmembrane domain tethered to the PKLNK domain, members of the other two classes of PKLNKs are cytoplasmic in nature. The current classification scheme hopes to provide a convenient framework to classify the PKLNKs from other eukaryotes which would be helpful in deciphering their roles in cellular processes.
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PMID:Classification of nonenzymatic homologues of protein kinases. 1980 14


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