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 mitogen-activated protein kinase (MAPK) family is comprised of key regulatory proteins that control the cellular response to both proliferation and stress signals. In this study we investigated the factors controlling MAPK activation by H2O2 and explored the impact of altering the pathways to kinase activation on cell survival following H2O2 exposure. Potent activation (10-20-fold) of extracellular signal-regulated protein kinase (ERK2) occurred within 10 min of H2O2 treatment, whereupon rapid inactivation ensued. H2O2 activated ERK2 in several cell types and also moderately activated (3-5-fold) both c-Jun N-terminal kinase and p38/RK/CSBP. Additionally, H2O2 increased the mRNA expression of MAPK-dependent genes c-jun, c-fos, and MAPK phosphatase-1. Suramin pretreatment completely inhibited H2O2 stimulation of ERK2, highlighting a role for growth factor receptors in this activation. Further, ERK2 activation by H2O2 was blocked by pretreatment with either N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating that metal-catalyzed free radical formation mediates the initiation of signal transduction by H2O2. H2O2-stimulated activation of ERK2 was abolished in PC12 cells by inducible or constitutive expression of the dominant negative Ras-N-17 allele. Interestingly, PC12/Ras-N-17 cells were more sensitive than wild-type PC12 cells to H2O2 toxicity. Moreover, NIH 3T3 cells expressing constitutively active MAPK kinase (MEK, the immediate upstream regulator of ERK) were more resistant to H2O2 toxicity, while those expressing kinase-defective MEK were more sensitive, than cells expressing wild-type MEK. Taken together, these studies provide insight into mechanisms of MAPK regulation by H2O2 and suggest that ERK plays a critical role in cell survival following oxidant injury.
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PMID:Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. 862 53

Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity.
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PMID:Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. 869 50

The tyrosine kinases Flt4, Flt1, and Flk1 (or KDR) constitute a family of endothelial cell-specific receptors with seven immunoglobulin-like domains and a split kinase domain. Flt1 and Flk1 have been shown to play key roles in vascular development; these two receptors bind and are activated by vascular endothelial growth factor (VEGF). No ligand has been identified for Flt4, whose expression becomes restricted during development to the lymphatic endothelium. We have identified cDNA clones from a human glioma cell line that encode a secreted protein with 32% amino acid identity to VEGF. This protein, designated VEGF-related protein (VRP), specifically binds to the extracellular domain of Flt4, stimulates the tyrosine phosphorylation of Flt4 expressed in mammalian cells, and promotes the mitogenesis of human lung endothelial cells. VRP fails to bind appreciably to the extracellular domain of Flt1 or Flk1. The protein contains a C-terminal, cysteine-rich region of about 180 amino acids that is not found in VEGF. A 2.4-kb VRP mRNA is found in several human tissues including adult heart, placenta, ovary, and small intestine and in fetal lung and kidney.
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PMID:Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. 870 Aug 72

RET germline mutations were found to predispose to the development of three variants of multiple endocrine neoplasia type 2, MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). We have screened for RET mutations at exons 10, 11, 13, and 16 in leukocyte DNA extracted from 37 individuals, and have identified RET germline mutations in 12 affected individuals from 9 unrelated families. No RET germline mutation was found in 19 individuals with apparent sporadic diseases. We have also screened for RET mutations at exons 10, 11, and 16 in tumor DNA extracted from 13 freshly frozen medullary thyroid carcinomas (MTC). RET mutation was detected in every tumor, either inherited or sporadic, indicating that RET plays an important role in the development of both inherited and sporadic MTC. We initially screened for RET mutations by direct DNA sequencing of the genomic PCR products amplified from patients' leukocyte or tumor DNA. Recently, we utilized the "Cold SSCP" method, nonradioactive single-stranded conformation polymorphism analysis, to screen for RET mutations and have identified a novel mutation, a 6-bp deletion preceding the cysteine-634, in a sporadic MTC.
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PMID:RET mutation screening in MEN2 patients and discovery of a novel mutation in a sporadic medullary thyroid carcinoma. 873 82

MTC occurs sporadically or as part of multiple endocrine neoplasia type 2 (MEN 2) syndromes or as familial MTC (FMTC). 97% of the patients affected with MEN 2B show a germline mutation in codon 918 (exon 16) within the tyrosine kinase domain of the RET protooncogene. In 97% of MEN 2A patients, the germline mutation affects one of five cysteine codons within exons 10 and 11 in the extracellular domain. Only 65% of FMTC patients are found to have a germline mutation of RET. These mutations affect either the cysteine rich domain (as MEN 2A mutations) or codons 768 (exon 13) or 804 (exon 14) within the tyrosine kinase domain. In families affected with hereditary form of MTC, mutation analysis is now commonly used to determine genetic status. Individuals without the mutation would be considered unaffected and would not require further biochemical screening. Individuals who inherit the MEN 2 mutation would undergo biochemical screening tests and have thyroidectomy as soon as these tests are abnormal. Risk of phaeochromocytoma in affected patients depends on the position of RET mutation. This risk is high if the patient has a codon 634 mutation and low if he has a mutation within exon 10, 13 or 14. Frequency of adrenal follow-up could so be adapted with regards to the localisation of RET germline mutation. When a new MTC case is diagnosed, the distinction between a true sporadic and a de novo hereditary case is important for future clinical management of both the patient and his family. The absence of RET exons 10, 11, 13, and 14 germline mutations appears to rule out MEN 2A to a high probability. However the presence of a familial form of MTC cannot be excluded conclusively. Since codon 918 somatic mutations are found in 25% of MTC from truly sporadic cases, mutation analysis of RET in tumour DNA may help in distinguishing the sporadic cases from those that are in fact heritable.
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PMID:[Analysis of the RET gene and medullary cancer of the thyroid. Contribution to the diagnosis and treatment]. 873 83

Using a PCR-based screen to identify tyrosine kinases involved in T cell development, we have cloned a new member of the Eph-family of receptor tyrosine kinases (Mep, for murine eph-family protein). At the amino acid level Mep is 60% identical to the chicken embryonic kinase Cek9. Sequence analysis indicates that the predicted extracellular portion of Mep bears an Ig-like domain, a cysteine-rich region, and sequences homologous to fibronectin type III. The transmembrane region of Mep is followed by a kinase domain. Surprisingly, this kinase domain carries amino acid substitutions in the highly conserved consensus motifs found in all protein tyrosine kinases and known to be crucial for kinase activity. We demonstrate that a bacterial fusion protein of the Mep kinase domain does not have protein tyrosine kinase activity. Analysis of Mep mRNA levels in a variety of mouse tissues shows that Mep is highly expressed in thymus and brain. We have also isolated two additional Mep cDNA clones from thymocytes which are predicted to encode secreted forms of the Mep extracellular domain; mRNAs encoding these secreted isoforms are also expressed in mouse brain.
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PMID:A new member of the Eph family of receptors that lacks protein tyrosine kinase activity. 876 Dec 99

To assess the feasibility of screening for multiple endocrine neoplasia type 2A (MEN 2A), the authors used DNA sequence analysis to evaluate the RET proto-oncogene in a kindred with MEN 2A. The kindred consisted of 95 members (1 to 79 years of age) and their spouses, and spanned five generations. Genomic DNA was extracted from peripheral blood lymphocytes or lymphoblastoid cell lines established from the family members, and the RET gene was amplified by polymerase chain reaction (PCR) using RET-specific primers (10q 11.2) and was sequenced. Periodic endocrine screening also was performed, by measuring the plasma calcitonin concentration after provocation with pentagastrin (0.5 microgram/kg intravenously) to assess its reliability for detecting the associated neoplasms. Nineteen patients were confirmed to have MEN 2A by medical records or the screening program. The DNA sequence of the PCR products from clinically established MEN 2A patients showed a mutation at codon 634 (TGC-->CGC) that resulted in an amino acid change from cysteine to arginine. Endocrine screening tests showed that six other family members had a mutated RET protooncogene. DNA sequencing can detect high-risk cases at a preclinical stage of the disease. The establishment of mutated MEN 2A gene carriers allows pediatric surgeons to consider total thyroidectomy at a very early stage of neoplasm development (C-cell hyperplasia) or even prophylactically.
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PMID:Germline mutations of the RET proto-oncogene in pedigree with MEN type 2A: DNA analysis and its implications for pediatric surgery. 878 1

The fibroblast growth factor receptors (FGFRs) are a family of receptor protein tyrosine kinases that have been shown to mediate a variety of cellular processes including angiogenesis, wound healing, tumorigenesis, and embryonic development. Distinct FGFR mutations in individuals with autosomal dominant disorders of bone growth and development provide a unique opportunity to determine the function of FGFRs during embryonic development. To determine the consequences of these mutations on receptor function, we have made mutations in Xenopus FGFR1 (XFGFR1) and FGFR2 (XFGFR2) that correspond to several of the mutations identified in these dysmorphic syndromes. Analysis of mutant receptor proteins expressed in Xenopus oocytes indicates that all but one have elevated tyrosine kinase activity relative to their wild-type counterparts. Those mutations that give an unpaired cysteine residue in the extracellular domain result in intermolecular disulfide bond formation and covalent receptor dimerization. Microinjection of Xenopus embryos with RNA encoding mutant receptors with elevated tyrosine kinase activity results in ligand-independent induction of mesoderm in animal pole explants. Wild-type XFGFR1 and XFGFR2 do not induce mesoderm when injected at similar doses. Co-injection of RNA encoding a dominant negative FGF receptor, lacking the tyrosine kinase domain, together with RNA encoding various activated FGFRs inhibits mesoderm induction by a receptor activated by a transmembrane domain mutation or extracellular mutations that introduce an unpaired cysteine residue into the extracellular domain but does not inhibit mesoderm induction by receptors bearing a tyrosine kinase domain mutation. These results indicate that different point mutations may activate FGFRs by distinct mechanisms and that ligand-independent FGFR activation may be a feature in common to many skeletal disorders.
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PMID:Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains. 879 88

Overexpression of the Neu/ErbB-2 receptor tyrosine kinase has been implicated in the genesis of human breast cancer. Indeed, expression of either activated or wild-type neu in the mammary epithelium of transgenic mice results in the induction of mammary tumors. Previously, we have shown that many of the mammary tumors arising in transgenic mice expressing wild-type neu occur through somatic activating mutations within the neu transgene itself. Here we demonstrate that these mutations promote dimerization of the Neu receptor through the formation of disulfide bonds, resulting in its constitutive activation. To explore the role of conserved cysteine residues within the region deleted in these altered Neu proteins, we examined the transforming potential of a series of Neu receptors in which the individual cysteine residues were mutated. These analyses indicated that mutation of certain cysteine residues resulted in the oncogenic activation of Neu. The increased transforming activity displayed by the altered receptors correlated with constitutive dimerization that occurred in a disulfide bond-dependent manner. We further demonstrate that addition of 2-mercaptoethanol to the culture medium interfered with the specific transforming activity of the mutant Neu receptors. These observations suggest that oncogenic activation of Neu results from constitutive disulfide bond-dependent dimerization.
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PMID:Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. 879 21

We have recently determined that -Ile-Tyr- were the two critical residues as a peptide substrate for p60c-src protein tyrosine kinase (Lou, Q. et al., Lett. Peptide Sci., 1995, 2, 289). Here, we report on the design and synthesis of a secondary 'one-bead, one-compound' combinatorial peptide library based on this dipeptide motif (XIYXXXX, where X = all 19 eukaryotic amino acids except for cysteine). This secondary library was screened for its ability to be phosphorylated by p60c-src PTK using [gamma 32P]ATP as a tracer. Five of the strongest [32P]-labeled peptide-beads were identified and microsequenced: GIYWHHY, KIYDDYE, EIYEENG, EIYEEYE, and YIYEEED. A solid-phase phosphorylation assay was used to evaluate the structure-activity relationship of GIYWHHY. It was determined that Ile2, Tyr3, His5, and His6 were crucial for its activity as a substrate.
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PMID:Identification of GIYWHHY as a novel peptide substrate for human p60c-src protein tyrosine kinase. 880 33


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