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)

Using a polymerase chain reaction based strategy, we identified a novel transmembrane tyrosine kinase in CD34+ human bone marrow cells and a human hepatocellular carcinoma cell line, Hep3B. This protein, hepatoma transmembrane kinase or Htk, shares amino acid similarity with the EPH subfamily of tyrosine kinases. The HTK gene is located on human chromosome 7. The predicted 987-amino acid sequence of Htk includes a transmembrane region and signal sequence. In the predicted extracellular domain, a cysteine-rich region and tandem fibronectin type III repeats are present while a single uninterrupted catalytic domain is present in the intracellular domain. These features are consistent with other members of the Eph subfamily. Antibodies raised against Htk extracellular domain immunoprecipitated a 120-kDa protein from either in vitro translated HTK or Hep3B cells which localized primarily to the Hep3B membrane subcellular fraction. Purified in vitro translated Htk was enzymatically active and autophosphorylated on tyrosine in kinase assays. Furthermore, antibodies against Htk ECD were agonistic, inducing Htk tyrosine phosphorylation in transfected NIH3T3 cells. Northern blot analysis demonstrated a single HTK transcript abundantly present in placenta and in a range of primary tissues and malignant cell lines. HTK appears to be expressed in fetal but not adult brain and in primitive and myeloid but not lymphoid hematopoietic cells. The novel transmembrane protein, Htk, may function as a receptor with an expression pattern suggesting a role in events mediating differentiation and development.
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PMID:Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily. 818 4

Exposure of beta 2-adrenergic receptors to agonists causes a rapid desensitization of the receptor-stimulated adenylyl cyclase, associated with an increased phosphorylation of the receptor. Agonist-promoted phosphorylation of the beta 2-adrenergic receptor (beta 2AR) by protein kinase A and the beta-adrenergic receptor kinase (beta ARK) is believed to promote a functional uncoupling of the receptor from the guanyl nucleotide regulatory protein Gs. More recently, palmitoylation of Cys341 of the receptor has also been proposed to play an important role in the coupling of the beta 2-adrenergic receptor to Gs. Here we report that substitution of the palmitoylated cysteine by a glycine (Gly341 beta 2 AR) using site directed mutagenesis leads to a receptor being highly phosphorylated and largely uncoupled from Gs. In Chinese hamster fibroblasts (CHW), stably transfected with the human receptor cDNAs, the basal phosphorylation level of Gly341 beta 2AR was found to be approximately 4 times that of the wild type receptor. This elevated phosphorylation level was accompanied by a depressed ability of the receptor to stimulate the adenylyl cyclase and to form a guanyl nucleotide-sensitive high affinity state for agonists. Moreover, exposure of this unpalmitoylated receptor to an agonist did not promote any further phosphorylation or uncoupling. A modest desensitization of the receptor-stimulated adenylyl cyclase response was observed but resulted from the agonist-induced sequestration of the unpalmitoylated receptor and could be blocked by concanavalin A. This contrasts with the agonist-promoted phosphorylation and uncoupling of the wild type receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered phosphorylation and desensitization patterns of a human beta 2-adrenergic receptor lacking the palmitoylated Cys341. 838 52

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

Eph, Elk, and Eck are prototypes of a large family of transmembrane protein-tyrosine kinases, which are characterized by a highly conserved cysteine-rich domain and two fibronectin type III repeats in their extracellular regions. Despite the extent of the Eph family, no extracellular ligands for any family member have been identified, and hence, little is known about the biological and biochemical properties of these receptor-like tyrosine kinases. In the absence of a physiological ligand for the Elk receptor, we constructed chimeric receptor molecules, in which the extracellular region of the Elk receptor is replaced by the extracellular, ligand-binding domain of the epidermal growth factor (EGF) receptor. These chimeric receptors were expressed in NIH 3T3 cells that lack endogenous EGF receptors to analyze their signaling properties. The chimeric EGF-Elk receptors became glycosylated, were correctly localized to the plasma membrane, and bound EGF with high affinity. The chimeric receptors underwent autophosphorylation and induced the tyrosine phosphorylation of a specific set of cellular proteins in response to EGF. EGF stimulation also induced DNA synthesis in fibroblasts stably expressing the EGF-Elk receptors. In contrast, EGF stimulation of these cells did not lead to visible changes in cellular morphology, nor did it induce loss of contact inhibition in confluent monolayers or growth in semisolid media. The Elk cytoplasmic domain is therefore able to induce tyrosine phosphorylation and DNA synthesis in response to an extracellular ligand, suggesting that Elk and related polypeptides function as ligand-dependent receptor tyrosine kinases.
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PMID:Biological and biochemical activities of a chimeric epidermal growth factor-Elk receptor tyrosine kinase. 841 96

Recently, germline mutations in the RET proto-oncogene were found to be associated with multiple endocrine neoplasia (MEN) syndromes, MEN 2A, MEN 2B and Familial medullary thyroid carcinoma (FMTC). In patients with MEN 2A and FMTC different point mutations have been identified in exons 10 and 11 of the cysteine rich regions of RET. Patients with MEN 2B have a single point mutation (ATG to ACG) at codon 918 of RET. Therefore, a direct DNA testing has been developed to provide a highly accurate technique of detecting kindred members who have inherited a specific mutation associated with MEN 2A, MEN 2B or FMTC. In USA and Europe, prophylactic thyroidectomy has been performed on the basis of positive DNA testing, and the presence of a C-cell hyperplasia or a small medullary thyroid carcinoma was confirmed in each patient operated. Through nationwide survey in Japan, 233 patients with MEN 2 syndrome have been identified. They consisted of 180 MEN 2A, 18 MEN 2B, 13 FMTC and 22 unclassified patients. At follow-up, 47% of patients had recurrent medullary thyroid carcinoma and 5.7% of patients died of the disease. Genetic analysis was performed on 15 patients of 6 unrelated families in our series, and the results revealed that germinal mutations of RET as previously reported were also responsible for MEN 2 syndrome in Japanese. DNA analysis and prophylactic thyroidectomy for kindred members at risk for MEN 2 are likely to be beneficial in Japan as well.
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PMID:[Multiple endocrine neoplasia type 2A, type 2B and familial medullary thyroid carcinoma syndrome]. 853 31

Hereditary C-cell carcinoma is encountered in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and familial medullary thyroid carcinoma (FMTC). Mutations of the RET proto-oncogene are associated with all three diseases. To obtain an insight into the molecular heterogeneity of MEN 2 syndromes and FMTC in the Netherlands, probands of 20 MEN 2A families, two FMTC families, and seven MEN 2B families were analyzed by the polymerase chain reaction (PCR), DNA sequencing, and restriction enzyme digestion for abnormalities in the RET proto-oncogene. RET mutations were found in all cases. All MEN 2A families had a mutation involving one of five cysteine codons in exons 10 and 11 of RET. Two novel dinucleotide mutations and a de novo mutation were found. Both FMTC families had a mutation of the Cys at codon 618. All MEN 2B probands carried a Met to Thr mutation in exon 16. All mutations could be confirmed by restriction enzyme digestion of PCR amplicons. Identification of the RET mutation in the Dutch population with hereditary C-cell carcinoma facilitates genetic testing for families or individuals at risk for MEN 2A, FMTC, and MEN 2B.
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PMID:Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC: two novel mutations and one de novo mutation for MEN 2A. 855 49

Medullary thyroid carcinoma (MTC) is a malignancy of the thyroid C-cells that comprises 5-10% of all thyroid cancers. MTC occurs in both sporadic and familial forms, the latter making up 25% of all MTCs and being comprised of three distinct syndromes--multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). To date, screening for MTC has been performed using the pentagastrin stimulation test, which is a provocative test for calcitonin release. Germline mutations in the RET protooncogene have been identified in families manifesting these syndromes and genetic screening of individuals at risk of one of these syndromes has become integral to their clinical management. The majority of the mutations associated with MEN 2A and FMTC are tightly clustered in a cysteine-rich region of the RET receptor. A single mutation associated with MEN 2B is in the the tyrosine kinase domain of the RET receptor. Somatic mutations have been identified in the tumor tissue of individuals with sporadic MTC and may prove to be helpful markers in discerning the hereditary or sporadic nature of the MTC. There is general agreement that the primary operation for MTC should include total thyroidectomy and central neck lymph node clearance. The role of microdissection for recurrent disease awaits longitudinal evaluation. External radiotherapy, radionuclide therapy, and chemotherapy may have a role in palliation, but have not been proven to have a curative value. Prognostic factors are discussed.
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PMID:Medullary thyroid carcinoma: recent advances and management update. 856 82

The RET proto-oncogene codes for a receptor-type tyrosine-kinase with to date unknown ligand. Recently, germline point-mutations in RET cysteine codons of the extracellular cysteine-rich domain (encoded by exons 10 and 11) and in the tyrosine-kinase domain (encoded by exon 16) at codon 918, have been associated with the syndromes of multiple endocrine neoplasia (MEN) type 2A, MEN type 2B and familial medullary thyroid carcinoma (FMTC). In our recent studies we have analyzed tumor and germline DNA extracted from formalin-fixed and paraffin-embedded specimens of 45 patients and additional blood samples of 38 possible MEN 2 gene carriers for the presence of RET point mutations in exons 10 and 11 by non-radioactive single strand conformation polymorphism analysis (PCR-SSCP) and for exon 16 by heteroduplex gel electrophoresis. Mutational analysis was performed by fluorescence-based dideoxy terminator cycle sequencing of PCR-products with an automated DNA sequencer. Materials included 19 patients with MEN 2A associated tumors (13 medullary thyroid carcinomas, 6 pheochromocytomas), 3 patients with MEN 2B associated medullary thyroid carcinomas and 23 patients with clinically sporadic tumors (16 medullary thyroid carcinomas, 7 phenochromocytomas). In all 19 MEN 2A patients we found RET germline point-mutations either at cysteine codons 634 (14), 630 (1) in exon 11 or at codon 618 (4) in exon 10. All 3 MEN 2B patients demonstrated germline point mutations at codon 918 (Met-->Thr) in exon 16. In 2 patients with clinically sporadic medullary thyroid carcinomas we found a point mutation at codon 634 both in DNA of the tumor and normal tissue, indicating the presence of a de novo germline mutation. In 5 sporadic medullary thyroid carcinomas and 2 pheochromocytomas we found a somatic point mutations were identified in 11 patients. Our results indicate that mutational analysis of the RET proto-oncogene is not only suitable to identify and subtype MEN 2 gene carriers using blood DNA but also to distinguish sporadic from inherited medullary thyroid carcinomas and phenochromocytomas analyzing DNA extracted from archival tissue specimens.
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PMID:Rudolf-Virchow-Preis 1995. The role of RET proto-oncogene mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN 2) gene carriers and in the discrimination of sporadic and familial medullary thyroid carcinomas and pheochromocytomas. 860 Jun 71

Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The Flt4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the Flt4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds Flt4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where Flt4 is expressed.
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PMID:A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. 861

A fourth member of the diacylglycerol kinase (DGK) gene family termed DGK delta was cloned from the human testis cDNA library. The cDNA sequence contains an open reading frame of 3,507 nucleotides encoding a putative DGK protein of 130,006 Da. Interestingly, the new DGK isozyme contains a pleckstrin homology domain found in a number of proteins involved in signal transduction. Furthermore, the C-terminal tail of this isozyme is very similar to those of the EPH family of receptor tyrosine kinases. The primary structure of the delta-isozyme also has two cysteine-rich zinc finger-like structures (C3 region) and the C-terminal C4 region, both of which have been commonly found in the three isozymes previously cloned (DGKs alpha, beta and gamma). However, DGK delta lacks the EF-hand motifs (C2) and contains a long Glu- and Ser-rich insertion (317 residues), which divides the C4 region into two portions. Taken together, these structural features of DGK delta indicate that this isozyme belongs to a DGK subfamily distinct from that consisting of DGKs alpha, beta, and gamma. Increased DGK activity without marked preference to arachidonoyl type of diacylglycerol was detected in the particulate fraction of COS-7 cells expressing the transfected DGKdelta cDNA. The enzyme activity was independent of phosphatidylserine, which is a common activator for the previously sequenced DGKs. Northern blot analysis showed that the DGK delta mRNA (approximately 6.3 kilobases) is most abundant in human skeletal muscle but undetectable in the brain, thymus, and retina. This expression pattern is different from those of the previously cloned DGKs. Our results show that the DGK gene family consists of at least two subfamilies consisting of enzymes with distinct structural characteristics and that each cell type probably expresses its own characteristic repertoire of DGKs whose functions may be regulated through different signal transduction pathways.
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PMID:Molecular cloning of a novel diacylglycerol kinase isozyme with a pleckstrin homology domain and a C-terminal tail similar to those of the EPH family of protein-tyrosine kinases. 862 38


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