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)

CCL19 and CCL21 are endogenous agonists for the seven-transmembrane receptor CCR7. They are equally active in promoting G protein stimulation and chemotaxis. Yet, we find that they result in striking differences in activation of the G protein-coupled receptor kinase (GRK)/ss-arrestin system. CCL19 leads to robust CCR7 phosphorylation and beta-arrestin2 recruitment catalyzed by both GRK3 and GRK6 whereas CCL21 activates GRK6 alone. This differential GRK activation leads to distinct functional consequences. Although each ligand leads to beta-arrestin2 recruitment, only CCL19 leads to redistribution of beta-arrestin2-GFP into endocytic vesicles and classical receptor desensitization. In contrast, these agonists are both capable of signaling through GRK6 and beta-arrestin2 to ERK kinases. Thus, this mechanism for "ligand bias" whereby endogenous agonists activate different GRK isoforms leads to functionally distinct pools of beta-arrestin.
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PMID:Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. 1949 75

Internalization and intracellular trafficking of membrane proteins are now recognized as essential mechanisms that contribute to a number of cellular processes. Current methods lack the ability to specifically label the plasma membrane of a live cell, follow internalization of labeled membrane molecules, and conclusively differentiate newly formed membrane-derived vesicles from pre-existing endocytic or secretory structures in the cytoplasm. Here, we detail a visualization method for surface biotinylation of plasma membrane-derived vesicles that allows us to follow their progress from membrane to cytosol at specific time points. Using the transmembrane receptor RET as a model, we demonstrate how this method can be applied to identify plasma membrane-derived vesicle maturation, determine RET's presence within these structures, and monitor RET's recycling to the cell surface. This method improves on static and less discriminatory methods, providing a tool for analysis of real-time vesicle trafficking that is applicable to many systems.
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PMID:Direct visualization of vesicle maturation and plasma membrane protein trafficking. 1982 24

The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family alpha co-receptors (GFRalpha). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy.
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PMID:Targeting the RET pathway in thyroid cancer. 1993 98

Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
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PMID:Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. 2006 93

Gastrointestinal stromal tumours (GIST) are the commonest mesenchymal tumours of gastrointestinal organs accounting for 1-3% of all gastrointestinal neoplasms and almost 5% of all soft tissue sarcomas. Most GIST (95%) express transmembrane receptor KIT or CD117, CD34 (70%), vimentin (80%), specific smooth muscle and neurogenic markers (with different frequency). Up to 85% of the stromal tumours have mutations in the KIT gene (exones 9, 11, 13, 17) and 3-18% in the PDGFRA (platelet-derived growth factor receptor-alpha) gene (exones 12, 14, 18). Mutations are absent in 5% of KITand PDGFRA genes. Mutational status, mitotic index, size and location of the tumour are the most informative criteria for the choice of treatment strategy and prognosis of the disease.
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PMID:[Gastrointestinal stromal tumours: clinico-morphological features, pathogenesis and modern treatment strategies]. 2036 79

The vascular endothelial growth factor receptor, Flt1 is a transmembrane receptor co-expressed with an alternate transcript encoding a secreted form, sFlt1, that functions as a competitive inhibitor of Flt1. Despite shared transcription start sites and upstream regulatory elements, sFlt1 is in far greater excess of Flt1 in the human placenta. Phorbol myristic acid and dimethyloxalylglycine differentially stimulate sFlt1 compared to Flt1 expression in vascular endothelial cells and in cytotrophoblasts. An FLT1 minigene construct containing exon 13, 14 and the intervening region, recapitulates mRNA processing when transfected into COS-7, with chimeric intronic sFlt1 transcripts arising by intronic polyadenylation and other Flt1/sFlt1 transcripts by alternate splicing. Inclusion of exon 15 but not 14 had a modest stimulatory effect on the abundance of sFlt1. The intronic region containing the distal poly(A) signal sequences, when transferred to a heterologous minigene construct, inhibited splicing but only when cloned in sense orientation, consistent with the presence of a directional cis-element. Serial deletional and targeted mutational analysis of cis-elements within intron 13 identified intronic poly(A) signal sequences and adjacent cis-elements as the principal determinants of the relative ratio of intronic sFlt1 and spliced Flt1. We conclude that intronic signals reciprocally regulate splicing and polyadenylation and control sFlt1 expression.
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PMID:Alternate processing of Flt1 transcripts is directed by conserved cis-elements within an intronic region of FLT1 that reciprocally regulates splicing and polyadenylation. 2038 95

TGFbeta signaling is initiated by binding of growth factor ligand to two related single-pass transmembrane receptor serine/threonine kinases, known as the TGFbeta type I (TbetaRI) and type II (TbetaRII-ED) receptors. TbetaRII-ED is essential for all TGFbeta-induced signals. The DNA sequence encoding the extracellular domain of human TbetaRII-ED (TbetaRII-ED, residues 4-136) was synthesized from 20 oligonucleotides by polymerase chain reaction and cloned into plasmid pET-32a downstream to the gene of fusion partner thioredoxin immediately after the DNA sequence encoding enteropeptidase recognition site. High level expression ( approximately 1 gL(-1)) of thioredoxin/TbetaRII-ED fusion was achieved in Escherichia coli BL21(DE3) strain mainly in soluble form. The soluble thioredoxin/TbetaRII-ED fusion has been purified and refolded on Ni-NTA agarose. After cleavage of purified thioredoxin/TbetaRII-ED fusion by recombinant human enteropeptidase light chain (L-HEP) the target protein of TbetaRII-ED was separated from thioredoxin on Ni-NTA agarose. Fourteen milligrams of highly purified TbetaRII-ED without N- or C-terminal tags was yielded from 100mL cell culture. The purified preparation of TbetaRII-ED was highly homogenous, as shown by SDS-PAGE with silver staining, HPLC and mass spectroscopy analysis. The binding of TbetaRII-ED purified from E. coli to TGFbeta1 was shown to be comparable to commercial material purified from NSO cells. Recombinant TbetaRII-ED could be employed as an antagonist of TGFbeta1 and TGFbeta3 in vitro and in vivo as well as for therapy of fibrotic disorders and some types of cancer.
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PMID:An efficient method for expression in Escherichia coli and purification of the extracellular ligand binding domain of the human TGFbeta type II receptor. 2045 68

EGFR constitute an attractive target for tumor therapy, because it is a transmembrane receptor tyrosine kinase which is critically involved in tumorigenesis by stimulating cell proliferation and inhibiting apoptosis or other biological functions. The anti-tumor effects of targeted therapy by anti-EGFR monoclonal antibodies are mainly based on direct inhibition of the EGFR signal transduction pathway. In addition, monoclonal antibody has the potential advantage of recruiting immune effect or mechanisms to kill tumor cells. The pre-clinical and clinical data indicated that antibody-dependent cellular cytotoxicity (ADCC) contributes to tumor cell lysis by anti-EGFR monoclonal antibodies. Some polymorphisms in Fc gamma receptor genes have been shown to be a predictive marker for the efficacy of anti-EGFR antibodies. Continued research on the immunotherapeutic mechanisms of monoclonal antibodies will improve the efficacy of antibody-based targeted therapy for cancer.
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PMID:[Antibody-dependent cellular cytotoxicity in the immunotherapeutic mechanisms of anti-EGFR monoclonal antibody]. 2049 9

Two types of VEGFR-1 receptors have been characterized: a full-length transmembrane receptor and a truncated extracellular soluble isoform (sVEGFR-1). We report here the characterization, in normal and cancer cells, of a new family of intracellular isoforms of VEGFR-1 resulting from alternative initiation of transcription in intronic sequences of the gene. While the classical isoforms of VEGFR-1 were barely detectable in MDA-MB-231 breast cancer cells, one of the intracellular isoforms transcribed from intron 21 (i(21)VEGFR-1) was the main isoform expressed in these cells. The new transcript encodes for a protein that contains only the phosphotransferase domain and the carboxyterminal tail of VEGFR-1. Treatment of MDA-MB-231 cells with siRNA specific for the tyrosine domain of VEGFR-1 suppressed the expression of i(21)VEGFR-1, downregulated phosphorylation of Src at tyrosine 418, and reduced markedly the invasion capacity of these cells in vitro. Accordingly, overexpression of transfected i(21)VEGFR-1 in MDA-MB-231 cells upregulated the active form of Src and increased invasiveness of MDA-MB-231 cells. The expression of i(21)VEGFR-1 in MDA-MB-231 cells was inhibited by retinoic acid. Both, activation of Src and downregulation by retinoic acid, have been reported in other intracellular members of the Fms/Kit/PDGFR family of tyrosine kinases, particularly in the intracellular isoform of c-kit, analogous structurally to i(21)VEGFR-1 and frequently expressed in cancer cells.
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PMID:A novel intracellular isoform of VEGFR-1 activates Src and promotes cell invasion in MDA-MB-231 breast cancer cells. 2051 33

Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase of the ERBB2 family that has important roles in the proliferation and metastasis of tumor cells. It is frequently overexpressed in common solid tumors and has become a favored target for orally administered small-molecule tyrosine kinase inhibitors (TKI) and monoclonal antibody-based therapy. Gain-of-function somatic mutations of the EGFR tyrosine kinase domain have been associated with the response of some patients with non-small-cell lung carcinoma to TKIs. We evaluated three methods of EGFR mutation analysis to identify an optimal assay for clinical testing based on comparison of diagnostic sensitivity, technical difficulty, and cost (Tab. 1, Fig. 1, Ref. 12).
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PMID:A comparative study of EGFR mutation screening methods in non-small cell carcinoma of lung. 2080 39


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