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)

The receptors for insulin and insulin-like growth factor I (IGF-I) are closely related molecules, with an extracellular binding domain and an intracellular tyrosine kinase domain. The interaction of insulin and IGF-I with their respective receptors activates the receptor kinase domain, leading to the biological actions of the hormones. Since insulin generally regulates metabolic events and IGF-I generally regulates growth events, it is believed that structural differences in the tyrosine kinase domains of the two respective receptors may elicit different biological responses via different transmembrane signaling mechanisms. We studied the regulation of glycogen metabolism and amino acid uptake in human cultured HEP-G2 hepatoma cells, which have distinct receptors for both insulin and IGF-I. The receptor specificity of these responses was probed with specific monoclonal antibodies to both the insulin and IGF-I receptors. Stimulation of both [3H]glucose incorporation into glycogen and alpha-[3H]aminoisobutyric acid uptake by insulin was half-maximal at concentrations of 1-5 nmol/L. These effects were blocked by the insulin receptor monoclonal antibody MA-10, but not by the IGF-I receptor antibody alpha IR-3. Stimulation of both functions by IGF-I was half-maximal at concentrations of 1-5 nmol/L, and these effects were inhibited by alpha IR-3, but not by MA-10. These studies indicate that in HEP-G2 cells both insulin and IGF-I, via their own receptors, stimulate the same biological responses.
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PMID:Insulin and insulin-like growth factor I regulate the same biological functions in HEP-G2 cells via their own specific receptors. 283 99

NIH 3T3 cells, which express a small number of EGF (epidermal growth factor) receptors, are poorly responsive to EGF. However, when the same cells overexpress the cloned human EGF receptor (EGFR T17 cells), they display EGF-dependent transformation. In EGFR T17 cells (but not in the parental NIH 3T3 cells), EGF is shown here to trigger polyphosphoinositide hydrolysis as well as the generation of the ensuing intracellular signals, the increase in the cytosolic Ca2+ concentration ([Ca2+]i) and pH. EGF induced a large accumulation of inositol 1,4,5-trisphosphate, with a peak at 15-30 s and a slow decline thereafter. Other inositol phosphates (1,3,4-trisphosphate and 1,3,4,5-tetrakisphosphate) increased less rapidly and to a lesser degree. [Ca2+]i increased after a short lag, reached a peak at 25 s and remained elevated for several minutes. By use of incubation media with and without Ca2+, the initial phase of the EGF-induced [Ca2+]i increase was shown to be due largely to Ca2+ release from intracellular stores. In contrast with previous observations in human A431 cells, the concentration-dependence of the EGF-triggered [Ca2+]i increase in EGFR T17 cells paralleled that of [3H]thymidine incorporation. It is concluded that polyphosphoinositide hydrolysis, [Ca2+]i increase and cytoplasmic alkalinization are part of the spectrum of intracellular signals generated by the activation of one single EGF receptor type. These processes might be triggered by the receptor via activation of the intrinsic tyrosine kinase activity. Large stimulation of DNA synthesis and proliferation by EGF in EGFR T17 cells could be due to a synergistic interplay between the two signal pathways initiated by tyrosine phosphorylation and polyphosphoinositide hydrolysis.
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PMID:Transmembrane signalling at epidermal growth factor receptors overexpressed in NIH 3T3 cells. Phosphoinositide hydrolysis, cytosolic Ca2+ increase and alkalinization correlate with epidermal-growth-factor-induced cell proliferation. 284 45

The rat neu oncogene encodes a cell surface glycoprotein, p185, that possesses tyrosine kinase activity. The p185 polypeptide exhibits structural similarity to the epidermal growth factor receptor (EGFR) at both the deduced amino acid and nucleic acid level. However, the neu oncogene and the gene encoding the EGFR have been shown to reside on distinct chromosomes. Comparative analysis of the sequences of the normal neu cDNA and of the neu cDNA from neuroblastomas has revealed a single point mutation leading to a valine-to-glutamic acid substitution in the transmembrane anchoring domain. This mutation converts the neu gene to a transforming gene in rodents. In humans, the gene is called ERBB2 (also NGL and HER2), and amplification and over-expression of its products have been detected in certain tumors. The rat embryonal fibroblast cell line (Rat-1) appears to express both EGFR and cellular p185 polypeptides. We have found that EGF stimulates the phosphorylation of p185 in these cells at tyrosine as well as serine and threonine residues in a specific and dose-dependent manner. This activity occurs even though radiolabeled EGF cannot bind to immunopurified p185. The EGF effect is apparently unique since platelet-derived growth factor, insulin, and transforming growth factor beta all fail to phosphorylate p185 at tyrosine. The EGF-induced effect requires interaction of the EGFR and its cognate ligand because cell lines that lack EGFR cannot be shown to phosphorylate p185, even when exposed to large amounts of EGF. Oncogenic rodent p185 and the human p185 homologue ERBB2 that is overexpressed in human breast tumor cells also can be shown to become phosphorylated on tyrosine residues by the action of EGF. Collectively, these data demonstrate that EGF mediates phosphorylation of p185 at tyrosine as well as serine/threonine through cellular kinases by a receptor-specific mechanism.
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PMID:Phosphorylation process induced by epidermal growth factor alters the oncogenic and cellular neu (NGL) gene products. 289 89

The protein encoded by the neu protooncogene (human gene symbol NGL for neuro/glioblastoma-derived) is a member of the surface receptor/tyrosine kinase family. Though its structure suggests that it can transduce a transmembrane signal, neither its extracellular ligand nor its critical intracellular substrates are known. To explore the functional properties of the protein encoded by neu, we created a fusion gene that joins the cytoplasmic domain of neu to the extracellular portion of an immunoglobulin heavy chain. The localization of the fusion polypeptide can then be controlled by coexpression with immunoglobulin light chain. In the absence of light chain, the heavy chain-neu polypeptide is expressed intracellularly and has no transforming activity. By contrast, in the presence of light chain the fusion polypeptide is expressed at the cell surface and produces tumorigenic foci. Thus, transformation apparently requires expression at the cell surface, where the neu intracellular domain can interact with components that are localized to the plasma membrane. The fusion protein is active in cellular transformation when the transmembrane domain is derived either from neu or from immunoglobulin, indicating that the neu transmembrane domain is not specifically required for transformation, although neu activation in tumors is known to result from a point mutation in this region. The extracellular immunoglobulin heavy and light chain domains of the fusion protein form a functional binding site that allows antigen to modulate its activity, reversing the transforming effect.
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PMID:neu protooncogene fused to an immunoglobulin heavy chain gene requires immunoglobulin light chain for cell surface expression and oncogenic transformation. 290

The human insulin receptor gene, INSR, and its promoter region have been isolated and characterized. The gene spans greater than 120 kilobase pairs (kbp) and has 22 exons. All introns interrupt protein coding regions of the gene. The 11 exons encoding the alpha subunit of the receptor are dispersed over greater than 90 kbp, whereas the 11 exons encoding the beta subunit are located together in a region of approximately 30 kbp. Three transcriptional initiation sites have been identified and are located 276, 282, and 283 bp upstream of the translation initiation site. In addition, a 247-bp fragment from the promoter region possessing 62.6% of the maximal promoter activity has been identified. This promoter-active fragment lacks a TATA-like sequence but has two possible binding regions for the transcriptional factor Sp1. Comparison of the exon structure of the tyrosine kinase domain of the INSR with the corresponding regions of the human SRC, ROS, and ERBB2 (NGL) protooncogenes indicates that the exon-intron organization of this region has not been well conserved.
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PMID:Structure of the human insulin receptor gene and characterization of its promoter. 291 61

A region of the primary amino acid sequence of the epidermal growth factor receptor (EGF) protein-tyrosine kinase, which is involved in ATP binding, was identified using chemical modification and immunological techniques. EGF receptor was 14C-labelled with the ATP analogue 5'-p-fluorosulphonylbenzoyladenosine and from a tryptic digest a single radiolabelled peptide was isolated. The amino acid sequence was determined to be residues 716-724 and hence lysine residue 721 is located within the ATP-binding site. Antisera were elicited in rabbits to a synthetic peptide identical to residues 716-727 of the EGF receptor and the homologous sequence in v-erb B transforming protein from avian erythroblastosis virus. The affinity-purified antibodies precipitated human ECF receptor from A431 cells and placenta, and the v-erb B protein from erythroblasts. The antibodies inhibited EGF-stimulated receptor protein-tyrosine kinase autophosphorylation and phosphorylation of an exogenous peptide substrate containing tyrosine. The antibodies did not immunoprecipitate the transforming proteins pp60v-src or P120gag-abl or cAMP-dependent protein kinase, proteins which have homologous but not identical sequences surrounding the lysine residue within the ATP-binding site, nor did they react with the platelet-derived growth factor receptor. The antibodies had no effect on the kinase activity of purified v-abl protein in solution. The antibodies may therefore be a specific inhibitor of the tyrosine kinase of the EGF receptor.
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PMID:Antibodies to the ATP-binding site of the human epidermal growth factor (EGF) receptor as specific inhibitors of EGF-stimulated protein-tyrosine kinase activity. 301 11

The proteins encoded by the human TPR-MET oncogene (p 65tpr-met) and the human MET protooncogene (p140met) have been identified. The p65tpr-met and p140met, as well as a truncated TPR-MET product expressed in Escherichia coli, p50met, are autophosphorylated in vitro on tyrosine residues. Using the immunocomplex kinase assay, p140met activity was detected in various human tumor epithelial cell lines. In vivo, p65tpr-met is phosphorylated on both serine and tyrosine residues, while p140met is phosphorylated on serine and threonine. p140met is labeled by cell-surface iodination procedures, suggesting that it is a receptor-like transmembrane protein-tyrosine kinase.
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PMID:Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases. 327 71

The neu oncogene (also referred to as c-erbB-2 and HER2) encodes a 185-kDa transmembrane glycoprotein with tyrosine kinase activity termed p185. The p185 glycoprotein is structurally related to the epidermal growth factor receptor. It is thought that p185 is the receptor for an as yet unidentified growth factor. In the present study, RNA blot analyses and immunohistochemical studies were performed on rat tissues obtained from a variety of prenatal and postnatal stages to examine the expression of the neu oncogene and its product, p185, during normal development. Expression of the neu gene was detected in mid-gestation embryos in a variety of tissues including nervous system, connective tissue, and secretory epithelium, but not in lymphoid tissue. In adult animals, secretory epithelial tissues and basal cells of the skin expressed neu. These studies demonstrate that the neu gene is expressed in a tissue- and developmental stage-specific manner. We suggest that the p185 molecule plays an important role in the growth and development of a variety of tissues, and, in particular, in epithelial tissue.
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PMID:Stage- and tissue-specific expression of the neu oncogene in rat development. 331 11

Transfection of NIH 3T3 cells with cDNA clones containing either the entire coding sequences or the tyrosine protein kinase domain of the human TRK protooncogene results in the frequent generation of transforming genes. Activation of most of these TRK oncogenes involves acquisition of DNA sequences. These sequences, unlike those present in the original human TRK oncogene, are not derived from tropomyosin genes. The products of these in vitro-generated TRK oncogenes retain the parental tyrosine protein kinase activity and contain an intact carboxyl terminus. However, they exhibit distinct biochemical properties. Whereas some of them are nonglycosylated cytoplasmic molecules, others were found to be transmembrane glycoproteins. These results suggest that TRK oncogenes may induce malignant transformation by allowing their tyrosine kinase to interact with various substrates depending on the nature of their activating sequences. If so, the TRK kinase may serve as a pleiotropic marker to identify various cellular proteins whose unscheduled phosphorylation on tyrosine residues contributes to neoplastic transformation.
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PMID:Frequent generation of oncogenes by in vitro recombination of TRK protooncogene sequences. 336 59

Ligand dependent activation of receptor tyrosine kinases is mediated by an allosteric dimerization process that is responsible for the stimulation of protein tyrosine kinase activity and receptor autophosphorylation. In order to gain further insight into the processes which control this process, we have generated EGF receptor mutants that contain inserts of 20-40 amino acids in their juxtamembrane regions, on each side of the receptor's single transmembrane domain. An EGF receptor mutant with an insertion on the cytoplasmic side of the transmembrane domain exhibited typical EGF binding characteristics, ligand-dependent tyrosine autophosphorylation, as well as ligand-induced DNA synthesis. However, an EGF receptor mutant with an insertion on both sides of the transmembrane domain was found to be constitutively activated. This mutant also exhibited dramatically reduced EGF binding, but dimerized and had enhanced tyrosine kinase activity even in the absence of ligand. Moreover, NIH3T3 cells expressing this mutant receptor formed colonies in soft agar in the absence of EGF. This represents a novel example of a constitutively activated receptor, and provides further support for receptor dimerization as a mechanism for activation of EGFR and other receptor tyrosine kinases.
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PMID:Activation of the EGF receptor by insertional mutations in its juxtamembrane regions. 747 77


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