Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MEK, a dual specificity threonine/tyrosine kinase, has been postulated to be a convergent point for signaling from receptor protein tyrosine kinases (RTKs) and G-protein-coupled receptors. In contrast to yeast and mammalian cells where several MEKs have been isolated, only one Drosophila MEK (D-Mek) has been characterized to date. Previous studies have shown that D-Mek acts in the Torso RTK signaling pathway. To demonstrate that D-Mek also operates downstream of other RTKs, we generated a temperature-sensitive allele of D-mek (D-mekts) by site-directed mutagenesis based on the amino acid change of a yeast cdc2ts mutation. Using D-mekts, we show that in addition to its role in Torso signaling, D-Mek operates in the Sevenless and in the Drosophila epidermal growth factor RTK pathways. Because loss-of-function mutations in D-mek and the upstream receptors give rise to similar phenotypes, it suggests that D-mek is the only MEK activated by Drosophila RTKs. In addition, we demonstrate that different RTK pathways respond differently to alteration in D-Mek activity.
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PMID:A temperature-sensitive MEK mutation demonstrates the conservation of the signaling pathways activated by receptor tyrosine kinases. 795 87

In normal, differentiating skin, hemidesmosomes make the stable attachment of basal epidermal keratinocytes to the dermis by linking the cytoplasmic keratin intermediate filaments to components of the basal lamina. In contrast, laterally migrating and proliferating basal keratinocytes in culture and presumably in repairing wounds use focal adhesions to form dynamic attachments to the dermis by linking actin microfilaments to the extracellular matrix. Focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase concentrated along with phosphotyrosine-containing proteins in the focal adhesions of some cultured cells, is activated in vitro when cells attach, form focal adhesions, and spread. This report finds that FAK is activated, as determined from its increased phosphotyrosine content and from its increased labeling with [gamma-32P]ATP, in immunoprecipitates from human cultured keratinocytes attached and spreading on fibronectin compared to those attached but not spreading on polylysine. Furthermore, immunofluorescence shows that both FAK and phosphotyrosine are concentrated in the focal adhesions of cultured keratinocytes attached and spreading on extracellular matrix components known to facilitate cellular migration (fibronectin, collagens I or IV, and epiligrin). Finally, immunohistochemistry localizes FAK to the epidermal-dermal junction in repairing partial thickness burn wounds. FAK is found at the epidermal-dermal junction at sites and times which coincide with actively migrating or rapidly proliferating basal keratinocytes, suggesting that this distribution represents FAK concentrated and activated in adhesions analogous to the focal adhesions seen in cultured cells. Hence, FAK appears to have an important in vivo role in the reepithelialization of human wounds.
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PMID:Potential role for focal adhesion kinase in migrating and proliferating keratinocytes near epidermal wounds and in culture. 798 54

We previously demonstrated that the gene tyk2 rescues the phenotype of a human mutant cell line unresponsive to alpha (IFN) and partially responsive to IFN-beta. Here, we describe functional complementation of the mutant cells with the corresponding cDNA. To characterize the putative non-receptor protein tyrosine kinase encoded by the gene tyk2 and begin to understand its functioning, we have raised polyclonal antibodies against a segment of the protein. Using these, we have identified tyk2 as a 134-kDa protein which is rapidly and transiently phosphorylated on tyrosine in response to IFN-alpha/beta and possesses an inducible kinase activity when tested in vitro. IFN-gamma has no effect on the phosphorylation state of the protein. In agreement with previous genetic evidence, these results assign a role to tyk2 in the IFN-alpha/beta signalling pathway and not in the IFN-gamma pathway. Fractionation of cell lysates have helped to localize the bulk of the protein in the cytoplasm, with a minor fraction associated with the cell membrane. Both protein pools undergo activation upon short-term IFN treatment of intact cells. Through the study of the effect of pervanadate on the phosphorylation level and the activity of tyk2, we conclude that activation of tyk2 by IFN-alpha does not require an intermediate regulatory tyrosine phosphatase.
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PMID:Activation of the protein tyrosine kinase tyk2 by interferon alpha/beta. 805 12

Dianilinophthalimides represent a novel class of inhibitors of the EGF-receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Steady-state kinetic analysis of compound 3, which showed potent inhibitory activity, revealed competitive type kinetics relative to ATP. Despite a highly symmetrical structure of compound 3, X-ray studies revealed an unsymmetrical propeller-shaped conformation of the molecule which differs clearly from that of the constitutionally related staurosporine aglycons. These conformational differences may explain the reversal of the selectivity profile of compound 3 relative to the staurosporine aglycons. In cellular assays compounds 3 and 4 have been shown to inhibit EGF-induced receptor autophosphorylation, c-fos induction and EGF-dependent proliferation of Balb/c MK cells. This inhibition was selective as compounds had no effect on PDGF-induced receptor autophosphorylation and c-fos induction. Furthermore, compound 3 showed potent antitumor activity in vivo at well-tolerated doses.
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PMID:Dianilinophthalimides: potent and selective, ATP-competitive inhibitors of the EGF-receptor protein tyrosine kinase. 815 12

The gene defective in X-linked agammaglobulinemia (XLA) has recently been isolated and identified as btk, a non-receptor protein tyrosine kinase. We have utilized the technique of single strand conformation polymorphism (SSCP) analysis for the btk gene to identify mutations in XLA patients. The btk gene in affected boys from 10 families was analysed and mutations were identified in eight cases; seven of these were point mutations and one was a small insertion. The mutations were found throughout the gene coding region. Six of the patients have classical XLA and two have less severe forms of the disease. We have also identified a polymorphism at nucleotide position 2031. This technique will allow us to provide more accurate diagnoses of the disease and to determine the nature of the functional defects in the btk gene in these families.
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PMID:Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. 816 56

Using a polymerase chain reaction-mediated approach we have characterized cDNAs from human and mouse origin representing a novel type of receptor protein tyrosine kinase (RTK). The deduced amino acid sequence (855 amino acids) of the longest open reading frame has a unique extracellular region encompassing a factor VIII-like domain, not previously described for RTKs. The most closely related RTKs are members of the neurotrophin receptors (TRK), which showed 47-49% homology with the kinase domain of the new RTK. Therefore, the new gene has been called TKT (Tyrosine-Kinase related to TRK). TKT orthologs from man and mouse were 98% similar. In both species a major transcript of 10 kb was found to be expressed at high levels in heart and lung. Low levels of this mRNA-species were detected in human brain, placenta, liver, skeletal muscle, kidney and in mouse brain and testis. Analysing human/mouse somatic cell hybrids we demonstrated that TKT segregates with human chromosome 1.
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PMID:Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain. 824 48

The Src homology (SH) region 2 binds to phosphorylated tyrosine residues and SH3 domains may interact with cytoskeletal molecules and GTPase-activating proteins for Rho/Rac proteins (the small GTP-binding proteins related to Ras). The recently cloned Ash/Grb-2 protein, a 25-28 kDa molecule composed entirely of SH2 and SH3 domains, is a mammalian homolog of the Caenorhabditis elegans Sem-5 protein, which communicates between a receptor protein tyrosine kinase and a Ras protein. In the present study the function of Ash/Grb-2 was investigated by microinjecting cells with an anti-Ash antibody. The antibody abolished both S phase entry and the reorganization of actin assembly to ruffle formation upon stimulation with epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). On the other hand, anti-Ash antibody had no effect on S phase entry or actin stress fiber formation induced by either serum or lysophosphatidic acid. Since the induction of DNA synthesis, ruffle induction and stress fiber formation involve a function of Ras, Rac activation and Rho activation respectively, the findings strongly suggest that Ash plays a critical role in the signaling of both pathways downstream from growth factor receptors to Ras and Rac. Consistent with this, Ash co-precipitated with EGF receptor from EGF-stimulated cells. Other proteins of approximately 21, 29, 135 and 160 kDa were also detected in the anti-Ash antibody immunoprecipitates, suggesting a role of Ash as a linker molecule in signal transduction downstream of growth factor receptors.
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PMID:Ash/Grb-2, a SH2/SH3-containing protein, couples to signaling for mitogenesis and cytoskeletal reorganization by EGF and PDGF. 825 73

Recent data support the existence of activation motifs within different subunits of the T-cell-receptor-CD3 complex. This architecture generates a receptor composed of discrete modules, each capable of being coupled to an effector pathway. Although new T-cell specific protein tyrosine kinases have recently been identified, the nature of the proximal non-receptor protein tyrosine kinase linking the T-cell receptor complex to essential signalling effectors remains unknown. Developmentally regulated differences in T-cell-receptor-CD3 assembly or stability may lead to the expression of isoforms displaying different sets of activation motifs. Whether this may be the basis of differential signalling during T-cell development is still a matter of speculation.
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PMID:Transmembrane signalling through the T-cell-receptor-CD3 complex. 834 95

Annexin I is a member of the annexin family of Ca(2+)- and phospholipid-binding proteins. The ability of this protein to aggregate and to mediate the fusion of various types of vesicles has supported the hypothesis that this protein might be involved in intracellular membrane fusion processes such as exocytosis. Although annexin I has been described as a major in vitro substrate of both protein kinase C and the epidermal-growth-factor-receptor protein tyrosine kinase, the functional consequences of these phosphorylation events have not been investigated. In this paper we examine the effect of the phosphorylation of annexin I by protein kinase C on the phospholipid aggregation activity of the protein. The stoichiometry of phosphorylation of the protein was affected by the method of preparation of the phospholipid. Under optimal assay conditions protein kinase C catalysed the incorporation of 2.83 +/- 0.23 mol of phosphate/mol of annexin I (mean +/- S.E.M., n = 21). Studies with the Ca(2+)- and phospholipid-independent form of protein kinase C suggested that the phosphorylation of annexin I was stimulated by phospholipid in the absence of Ca2+, although maximal phosphorylation was achieved in the presence of both phospholipid and Ca2+. Phosphorylation of annexin I resulted in a dramatic decrease in the rate and extent of phospholipid vesicle aggregation, without significantly disrupting the binding of the protein to the phospholipid vesicles. The phosphorylation of annexin I increased the EC50 (Ca2+) of phospholipid vesicle aggregation from 19 +/- 10 microM (mean +/- S.D., n = 7) for the native protein to 290 +/- 95 microM (mean +/- S.D., n = 5) for the phosphorylated protein. These results suggest that protein kinase C may act to inhibit the phospholipid vesicle aggregation activity of annexin I.
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PMID:Regulation of annexin I-dependent aggregation of phospholipid vesicles by protein kinase C. 837 35

Using a polymerase chain reaction-based approach we have isolated and characterized a cDNA (HPK-6) from human placental RNA encoding a novel receptor protein tyrosine kinase. This receptor tyrosine kinase has a unique extracellular domain, with an immunoglobulin-like domain at the amino terminus followed by three EGF-like cysteine repeats and three fibronectin type III repeats, giving the HPK-6 gene extracellular domain a novel combination of structural motifs. A comparison of the HPK-6 sequence with other receptor tyrosine kinases shows that the HPK-6 gene is the human homolog of the murine tek gene and very closely related to the recently described receptor tyrosine kinase tie. The HPK-6 gene is expressed predominantly in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney. The HPK-6 cDNA, when transfected into COS-7 cells, encodes a 140-kDa protein with in vitro kinase activity.
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PMID:Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. 838 58


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