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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Src homology regions 2 (SH2) and 3 (SH3) are noncatalytic domains that are conserved among several proteins implicated in the regulation of cell proliferation. Using bacterially expressed fusion proteins containing the SH2 domain of the abl tyrosine kinase, we have quantitated the binding of these domains to the activated epidermal growth factor (EGF) receptor (EGFR). A 35S-labeled abl SH2 fusion protein binds to the human EGFR immunoprecipitated from EGF-treated NIH3T3 cells that overexpress the receptor. This binding is totally dependent on the pretreatment of cells with EGF. The interaction is rapid, reaching 50% of maximum within 1 min, and attaining apparent equilibrium by 10 min. Dissociation of the complex is biphasic with a rapidly dissociating component (t1/2 of less than 1 min), as well as a slowly dissociable component. The 35S-labeled abl SH2 fusion protein specifically binds to the EGFR in a saturable manner and is differentially inhibited by unlabeled fusion proteins containing SH2 domains from phospholipase C, the p85 subunit of phosphatidylinositol-3 kinase, and the GTPase activation protein of ras. To identify residues critical for abl SH2-EGFR binding, six point mutants were constructed in the highly conserved FLVRES motif. Three mutants (V170L, E172Q, and E174Q) display binding affinities similar to that of wild type. However, three other mutants (R171K, S173C, and S175C) have greatly reduced affinity. Interestingly, the binding affinity to the EGFR determined by the in vitro assay directly correlates with the transforming ability of the corresponding v-abl constructs in vivo (Mayer, B. J., Jackson, P. K., Etten, R. A. V., and Baltimore, D. (1992) Mol. Cell. Biol. 12, 609-618). These data indicate that the Arg-171, Ser-173, and Ser-175 are critical for both transformation and abl SH2 domain binding to phosphotyrosine-containing proteins.
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PMID:Direct analysis of the binding of the abl Src homology 2 domain to the activated epidermal growth factor receptor. 767 9

Previous studies have demonstrated that the administration of epidermal growth factor (EGF) to neonatal mice results in the tyrosine phosphorylation of multiple substrates in all organs examined (Donaldson, R. W., and Cohen, S. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 8477-8481). One of these substrates, a 55-kDa protein, was shown to associate with the receptor for EGF (EGFR). We now report the identification of this receptor-associated protein as SHC. Immunoprecipitation and Western blotting analyses have revealed that SHC associates only with the activated EGFR. In the absence of EGF stimulation, SHC exists in the liver as a cytoplasmic monomer. Intraperitoneal injection of EGF results, within minutes, in the translocation of 50-80% of SHC to the liver plasma membrane. The membrane-associated SHC was found to be tyrosine-phosphorylated; the subsequent release of SHC from the membrane correlated with a tyrosine dephosphorylation. We conclude that SHC is a physiological substrate that appears to participate in the in vivo signaling response to EGF.
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PMID:Epidermal growth factor stimulates the tyrosine phosphorylation of SHC in the mouse. 768 24

Increased protein tyrosyl phosphorylation in response to growth factors has been assumed to be solely due to activation of protein tyrosine kinases (PTKs). We report that total cellular protein tyrosine phosphatase (PTPase) activity declined in MDA-MB 468 breast carcinoma cells exposed to epidermal growth factor (EGF). The PTPase activity decreased with concentration as well as with time of EGF incubation. As EGF induces increases in intracellular Ca2+ concentrations and such changes may result in depression of PTPase activity, we treated cells with the calcium ionophore A 23187. Increases in calcium induced by the ionophore resulted in activation of cellular PTPases as indicated by increased dephosphorylation of tyrosine phosphorylated EGFR by cellular lysates. Thus, both the extracellular ligand EGF and the intracellular messenger Ca2+ were shown to modulate cellular PTPase activity in MDA-MB 468 breast carcinoma cells. However, EGF-induced decreases in PTPase activity cannot be attributed to EGF-induced increases in intracellular Ca2+ levels.
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PMID:Role of intracellular Ca2+ in the epidermal growth factor induced inhibition of protein tyrosine phosphatase activity in a breast cancer cell line. 768 60

We have isolated rat cDNAs that encode two related receptor-like tyrosine kinases. One of these receptors, TIE-1, is the rat homolog of a recently described human receptor-like kinase termed TIE (Partanen et al., 1992). The related TIE-2 receptor has the same organization of amino acid sequence motifs characteristic of TIE-1: two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin III-like repeats in the extracellular region and a short kinase insert sequence and C-terminal tail in the intracellular region. The amino acid sequences of the intracellular and extracellular regions of TIE-1 and TIE-2 are 79% and 32% identical respectively. Both tie genes are broadly expressed in embryonic, neonatal and adult tissues, accounted for largely by their coexpression in endothelial cells. The tie-2 gene is also uniquely expressed in several additional embryonic tissues, including the lens epithelium and the heart epicardium.
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PMID:Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. 768 30

A putative mitogen-activated protein kinase (MAPK) has recently been identified, which potentially phosphorylates the human epidermal growth factor (EGF) receptor at a physiological site (Thr-669) and is distinguished from other MAPKs/extracellular signal-regulated protein kinases (ERKs) on the basis of chromatographic, immunological, and kinetic data. Here we report that this newly discovered MAPK is physically associated with the EGF receptor in A431 cells and with the related receptor/tyrosine kinase HER2 (encoded by c-neu) in enzyme preparations obtained from Wilm's tumors. This human EGF receptor-associated kinase is characterized as a 40-kDa Thr-669 kinase that exists in a high molecular mass complex with the respective growth factor receptor. EGF treatment of A431 cells stimulates the tyrosine phosphorylation of p40 and increases Thr-669 kinase activity in p40-containing fractions. The 40-kDa kinase is recognized by affinity-purified polyclonal antibodies directed against the sea star p44mpk and a Pan-ERK antibody directed against the conserved subdomain VIII of MAPKs/ERKs, but is not recognized by antibodies selective for the rat p44erk1 and/or the p42mapk/erk2 isoforms, thus identifying the EGF receptor-associated kinase as a novel MAPK that may regulate receptor function in vivo.
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PMID:Identification of a human epidermal growth factor receptor-associated protein kinase as a new member of the mitogen-activated protein kinase/extracellular signal-regulated protein kinase family. 768 42

An expression cloning method which allows direct isolation of cDNAs encoding substrates for tyrosine kinases was applied to the study of the epidermal growth factor (EGF) receptor (EGFR) signaling pathway. A previously undescribed cDNA was isolated and designated eps15. The structural features of the predicted eps15 gene product allow its subdivision into three domains. Domain I contains signatures of a regulatory domain, including a candidate tyrosine phosphorylation site and EF-hand-type calcium-binding domains. Domain II presents the characteristic heptad repeats of coiled-coil rod-like proteins, and domain III displays a repeated aspartic acid-proline-phenylalanine motif similar to a consensus sequence of several methylases. Antibodies specific for the eps15 gene product recognize two proteins: a major species of 142 kDa and a minor component of 155 kDa, both of which are phosphorylated on tyrosine following EGFR activation by EGF in vivo. EGFR is also able to directly phosphorylate the eps15 product in vitro. In addition, phosphorylation of the eps15 gene product in vivo is relatively receptor specific, since the erbB-2 kinase phosphorylates it very inefficiently. Finally, overexpression of eps15 is sufficient to transform NIH 3T3 cells, thus suggesting that the eps15 gene product is involved in the regulation of mitogenic signals.
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PMID:eps15, a novel tyrosine kinase substrate, exhibits transforming activity. 768 53

SH2 domains function to bind proteins containing phosphotyrosine and are components of proteins that are important signal transducers for tyrosine kinases. We have cloned SH2 domain proteins by screening bacterial expression libraries with the tyrosine phosphorylated carboxyterminus of the epidermal growth factor (EGF) receptor. Here we report the identification of a new SH2 domain protein, Grb10. Grb10 is highly related to Grb7, an SH2 domain protein that we have previously identified. In addition to an SH2 domain, Grb7 and Grb10 have a central domain with similarity to a putative C. elegans gene likely to be involved in neuronal migration. At least three forms of Grb10 exist in fibroblasts apparently due to alternate translational start sites. Grb10 undergoes serine but not tyrosine phosphorylation after EGF treatment resulting in a shift mobility in a large fraction of Grb10 molecules. However Grb10 appears to bind poorly to EGF-Receptor and the true binding partner for the Grb10 SH2 domain is unclear. Grb10 maps to mouse chromosome 11 very close to the EGF-Receptor which is remarkably similar to Grb7 that maps near the EGF-Receptor related HER2 receptor. The finding of multiple family members with evolutionarily conserved domains indicates that these SH2 domain proteins are likely to have an important, although as of yet, unidentified function.
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PMID:The cloning of Grb10 reveals a new family of SH2 domain proteins. 773 17

Heregulins (HRGs) are mosaic glycoproteins that bind to and induce the tyrosine phosphorylation of the HER4/p180erbB4 receptor. This work was aimed at studying the biological effects induced by recombinant epidermal growth factor (EGF)-like domains of HRGs as well as identifying intracellular molecules involved in HER4 signaling. To this end, we cloned the EGF-like domains of HRG-alpha, -beta 2, and -beta 3 into a eukaryotic expression vector in frame with sequences encoding a thrombin cleavage site followed by the Fc portion of a human IgG1. These chimeric genes directed the expression of recombinant fusion proteins, rHRGs-T-Fc, which specifically stimulated the phosphorylation of HER4/p180erbB4. We also show that rHRG-alpha-T-Fc bound to human breast cancer cells that express HER4 receptors and induced the expression of intercellular adhesion molecule-1. After thrombin protease cleavage of rHRGs-T-Fc, their EGF-like domains were purified and shown to stimulate protein phosphorylation in HER4-expressing cells. Moreover, the rHRG-beta 2 EGF-like domain markedly induced the phosphorylation of Shc proteins on tyrosine, suggesting a role for these adaptor molecules in HRG-mediated signaling.
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PMID:HER4 receptor activation and phosphorylation of Shc proteins by recombinant heregulin-Fc fusion proteins. 775 43

Insulin-stimulated glucose transport in adipocytes is mediated by the insulin receptor. To ascertain whether a related receptor could also trigger this response, the epidermal growth factor (EGF) receptor (EGFR) was introduced into adipocytes. 3T3-L1 fibroblasts were infected by a retroviral construct encoding either the full-length (WT) or a carboxy-terminal truncated (c'973) human EGFR; truncation of the amino acids distal to 973 removes all autophosphorylation motifs. After selection and conversion to adipocytes, the level of EGFR expression was retained in infectant adipocytes (150,000 and 250,000/cell, respectively), but not in the parental 3T3-L1 adipocytes (< 5000/cell). WT and c'973 EGFR exhibited ligand-dependent tyrosine kinase activity and stimulated mitogen-activated protein kinase activity equivalently; neither phosphorylated insulin receptor substrate-1. WT EGFR, but not c'973 EGFR, underwent ligand-induced autophosphorylation. EGF did not stimulate tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1. EGF had a minimal effect on glucose transport by parental 3T3-L1 adipocytes. Glucose transport in the WT EGFR adipocytes was stimulated equivalently by insulin and EGF; exposure to insulin and EGF in combination did not result in augmented transport. Glucose transport in the c'973 EGFR adipocytes was stimulated by insulin, but not by EGF. GLUT4 was translocated to the plasma membrane to a similar extent in response to insulin or EGF in the WT EGFR adipocytes; only insulin caused a significant GLUT4 translocation in the parental or c'973 EGFR adipocytes. These data suggest that the insulin and EGF signaling pathways that lead to glucose transport converge in these adipocytes down-stream of the insulin receptor, and that activation of this pathway requires signaling motifs in the carboxy-terminus of the EGFR. This model system represents a novel approach with which to dissect signal transduction pathways in terminally differentiated adipocytes.
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PMID:Epidermal growth factor (EGF) receptor carboxy-terminal domains are required for EGF-induced glucose transport in transgenic 3T3-L1 adipocytes. 783 73

Human tumors express high levels of growth factors and their receptors, and many types of malignant cells appear to exhibit autocrine- or paracrine-stimulated growth. Therefore, antireceptor directed therapies have the potential of being useful anti-cancer agents. A series of murine monoclonal antibodies (MAbs) directed against human growth factor receptors and their corresponding growth factors have been produced. MAbs against the receptors for epidermal growth factor, Her2/Neu, transferrin, insulin-like growth factor, interleukin, (IL)-2 and IL-1 are currently being evaluated. MAbs directed against epidermal growth factor, transforming growth factor-alpha, bombesin, IL-2, and IL-6 also are under study. These MAbs have shown promising preclinical activity, and some of them are being tested in clinical trials. So far, anti-tumor responses have been observed with anti-IL-2 receptor, anti-bombesin and anti-IL-6 MAbs. Further research is focusing in the production of "chimeric" and "humanized" MAbs, in order to obviate the problem of host immune reactions.
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PMID:Receptor blockade with monoclonal antibodies as anti-cancer therapy. 784 12


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