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)

Gastrointestinal stromal tumors (GISTs) may be defined as morphologically spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumours of the gastrointestinal tract that usually express the KIT protein and harbour mutation of a gene that encodes for a type III receptor tyrosine kinase (either KIT or PDGFRA). In Caucasian populations their annual incidence is 10 to 15 cases per million. Approximately 80% of GISTs have mutated KIT and 5% mutated PDGFRA. Most KIT mutations occur in untreated GISTs in the juxtamembrane exon 11 and only rarely in the kinase domain, whereas in imatinib-treated patients secondary mutations are frequent in exons encoding for the ATP/imatinib binding pocket or the kinase activation loop. Surgery is the standard treatment of local GIST. Tyrosine kinase inhibitor imatinib is the standard treatment for metastatic disease with few exceptions. A majority (80-90%) of patients with metastatic disease respond to imatinib or achieve durable tumour growth stabilisation with continuous therapy using a daily dose of 400 mg to 600 mg. Treatment with imatinib increases survival of patients with advanced disease with a few years and is associated with only moderate toxicity. Imatinib is being evaluated as adjuvant treatment following surgery, and other tyrosine kinase inhibitors as treatments of advanced GIST.
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PMID:Gastrointestinal stromal tumor (GIST). 1701 39

The Receptor Tyrosine kinase (RTK) and TGF-beta signaling pathways play essential roles during development in many organisms and regulate a plethora of cellular responses. From the genome sequence of Strongylocentrotus purpuratus, we have made an inventory of the genes encoding receptor tyrosine kinases and their ligands, and of the genes encoding cytokines of the TGF-beta superfamily and their downstream components. The sea urchin genome contains at least 20 genes coding for canonical receptor tyrosine kinases. Seventeen of the nineteen vertebrate RTK families are represented in the sea urchin. Fourteen of these RTK among which ALK, CCK4/PTK7, DDR, EGFR, EPH, LMR, MET/RON, MUSK, RET, ROR, ROS, RYK, TIE and TRK are present as single copy genes while pairs of related genes are present for VEGFR, FGFR and INSR. Similarly, nearly all the subfamilies of TGF-beta ligands identified in vertebrates are present in the sea urchin genome including the BMP, ADMP, GDF, Activin, Myostatin, Nodal and Lefty, as well as the TGF-beta sensu stricto that had not been characterized in invertebrates so far. Expression analysis indicates that the early expression of nodal, BMP2/4 and lefty is restricted to the oral ectoderm reflecting their role in providing positional information along the oral-aboral axis of the embryo. The coincidence between the emergence of TGF-beta-related factors such as Nodal and Lefty and the emergence of the deuterostome lineage strongly suggests that the ancestral function of Nodal could have been related to the secondary opening of the mouth which characterizes this clade, a hypothesis supported by functional data in the extant species. The sea urchin genome contains 6 genes encoding TGF-beta receptors and 4 genes encoding prototypical Smad proteins. Furthermore, most of the transcriptional activators and repressors shown to interact with Smads in vertebrates have orthologues in echinoderms. Finally, the sea urchin genome contains an almost complete repertoire of genes encoding extracellular modulators of BMP signaling including Chordin, Noggin, Sclerotin, SFRP, Gremlin, DAN and Twisted gastrulation. Taken together, these findings indicate that the sea urchin complement of genes of the RTK and TGF-beta signaling pathways is qualitatively very similar to the repertoire present in vertebrates, and that these genes are part of the common genetool kit for intercellular signaling of deuterostomes.
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PMID:RTK and TGF-beta signaling pathways genes in the sea urchin genome. 1708 34

Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so-called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5-cm-large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.
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PMID:Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? 1710 20

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs)--vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Sunitinib demonstrated robust antitumor activity in preclinical studies resulting not only in tumor growth inhibition, but tumor regression in models of colon cancer, non-small-cell lung cancer, melanoma, renal carcinoma, and squamous cell carcinoma, which were associated with inhibition of VEGFR and PDGFR phosphorylation. Clinical activity was demonstrated in neuroendocrine, colon, and breast cancers in phase II studies, whereas definitive efficacy has been demonstrated in advanced renal cell carcinoma and in imatinib-refractory GISTs, leading to US Food and Drug Administration approval of sunitinib for treatment of these two diseases. Studies investigating sunitinib alone in various tumor types and in combination with chemotherapy are ongoing. The clinical benchmarking of this small-molecule inhibitor of members of the split-kinase domain family of RTKs will lead to additional insights regarding the biology, potential biomarkers, and clinical utility of agents that target multiple signaling pathways in tumor, stromal, and endothelial compartments.
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PMID:Sunitinib: from rational design to clinical efficacy. 1760 94

In this report, we demonstrate the application of Au nanoparticles in the electrochemical detection of protein phosphorylation. The method is based on the labeling of a specific phosphorylation event with Au nanoparticles, followed by electrochemical detection. The phosphorylation reaction is coupled with the biotinylation of the kinase substrate using a biotin-modified adenosine 5'-triphosphate [gamma]-biotinyl-3,6,9-trioxaundecanediamine (ATP) as the co-substrate. When the phosphorylated and biotinylated kinase substrate is exposed to streptavidin-coated Au nanoparticles, the high affinity between the streptavidin and biotin resulted in the attachment of Au nanoparticles on the kinase substrate. The electrochemical response obtained from Au nanoparticles enables monitoring the activity of the kinase and its substrate, as well as the inhibition of small molecule inhibitors on protein phosphorylation. We determined the activity of Src non-receptor protein tyrosine kinase, p60(c-Src) and protein kinase A in combination with their highly specific substrate peptides Raytide EL and Kemptide, respectively. The detection limits for Raytide EL and Kemptide were determined as 5 and 10 microM, (S/N=3), and the detection limits for the kinase activity of p60(c-Src) and protein kinase A (PKA) were determined as 5 and 10 U mL(-1), (S/N=3), respectively. Tyrosine kinase reactions were also performed in the presence of a well-defined inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2), and its negative control molecule, 4-amino-7-phenylpyrazol[3,4-d] pyrimidine (PP3), which had no inhibition effect. Based on the dependency of Au nanoparticle signal on inhibitor concentration, IC(50) value, half-maximal inhibition of the inhibitors was estimated. IC(50) values of PP2, genistein and herbimycin A to p60(c-Src) were detected as 5 nM, 25 microM and 900 nM, respectively. The inhibition of PKA activity on Kemptide using ellagic acid was monitored with an IC(50) of 3.5 microM. The performance of the biosensor was optimized including the kinase reaction, incubation with streptavidin-coated Au nanoparticles, and the small molecule inhibitors. Kinase peptide-modified electrochemical biosensors are promising candidates for cost-effective kinase activity and inhibitor screening assays.
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PMID:Gold nanoparticle-based electrochemical detection of protein phosphorylation. 1738 90

Tyrosine kinase receptors (RTKs) are a heterogeneous group of transmembrane proteins involved in signal transduction. These receptors are expressed in many different cells and regulate cellular growth, differentiation and angiogenesis. Overexpression and/or the structural alteration of different RTKs classes are generally associated to cancer and, when RTKs-mediated signal transduction pathways are abnormally activated, generate cancer growth, angiogenesis and metastatization. Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies. Sunitinib malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs, which has both direct anticancer and antiangiogenetic activity. Sunitinib targets selectively vascular endothelial growth factor, KIT, Flt3 and platelet-derived growth factor receptors and the receptor encoded by the ret proto-oncogene. This drug is used in the treatment of gastrointestinal stromal cancer (GIST) resistant to imatinib and metastatic renal cell carcinoma (RCC). In this review, we report preclinical data of sunitinib, even about synergism with chemotherapy and radiotherapy, data relative to phase III trials of sunitinib in the treatment of GIST and RCC, and we try to plan what will be future applications of sunitinib in different types of cancer, even in association to chemotherapy, radiotherapy and monoclonal antibodies.
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PMID:Sunitinib: bridging present and future cancer treatment. 1759 28

A 27-year-old man was admitted due to abdominal fullness. He had ascites and subcutaneous nodules on his head, with liver dysfunction and eosinophilia. Abdominal imaging revealed obstruction of the hepatic veins and stenosis of the inferior vena cava. Histological diagnosis of a subcutaneous nodule revealed obstructive thrombophlebitis with eosinophils. Tyrosine kinase created by fusion of the FIP1L1 and PDGFRA genes, which is characteristic of hypereosinophilic syndrome (HES), was detected. He was diagnosed with Budd-Chiari syndrome associated with HES. Liver function tests improved after interventional therapy followed by steroid therapy. It is important to diagnose the cause of Budd-Chiari syndrome.
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PMID:Budd-Chiari syndrome associated with hypereosinophilic syndrome; a case report. 1763 6

New cancer-specific therapies are based on specific molecular alterations of malignant tumors which are targeted by small inhibitory molecules or specific antibodies. During the development of these agents potential molecular targets are characterized for their expression and importance for pathogenesis and clinical course of the disease. Frequently the assumption is made that the degree of expression of the target protein or the molecular alteration of the target gene allows a prediction if a certain patient will profit from the therapy against this specific protein or not. The first example was that breast cancer patients with overexpression and/or amplification of Her-2 respond to a Her-2-specific antibody (Herceptin) therapy. The expression or activation of the Epidermal Growth Factor Receptor (EGFR, Her-1) are altered in many epithelial tumours and clinical studies indicate that they have important roles in tumor aetiology and progression. Several EGFR-specific monoclonal antibodies and specific tyrosine kinase inhibitors were developed in the last years. Cetuximab is approved for the treatment of metastatic colorectal cancer and advanced squamous cell carcinoma of the head and neck and is investigated in numerous trials for other tumors. The expression of EGFR in the tumor was a prerequisite for the therapy in the first trials, giving the pathologist a central role in treatment decision. However, recent data clearly demonstrate that the degree of EGFR expression does not correlate with therapy response. Therefore a therapy should be not denied to a individual patient solely because of lack of EGFR expression in the tumor. Tyrosine kinase inhibitors (e. g. Gefitinib, Erlotinib) are effective in the treatment of non small cell lung cancer and also investigated in ongoing trials in many cancer types. The correlation of therapy response with both specific molecular alterations (EGFR tyrosine kinase domain mutations) and clinicopathological features (Asian ethnicity, women, non-smokers, bronchioloalveolar differentation) is a good example of the potential role of predictive molecular pathology in the future.
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PMID:[Role of predictive pathology in oncology--example of new therapies targeting EGFR]. 1786 89

Carcinomas of an unknown primary site (CUP) are heterogeneous tumours with a median survival of only 8 months. Tyrosine kinase inhibitors are promising new drugs. The aim of this study was to determine the expression of EGF-receptor, Her-2/neu, and c-Kit tyrosine kinases in CUP. Paraffin-embedded specimens were obtained from 54 patients with a CUP who were included in the GEFCAPI 01 randomised phase II trial. Immunohistochemistry was performed using the Dako autostainer with antibodies directed against HER-2/neu protein, EGFR protein, and c-Kit protein (CD117). EGFR expression was found in 36 out of 54 samples (66%). In contrast, Her-2/neu overexpression and c-Kit positivity were only detected in 4 and 10% of patients, respectively. No significant association was found between the expression of the tyrosine kinase receptors and prognosis. EGFR expression was significantly associated with response to cisplatin-based chemotherapy: the response rates were 50 and 22% in patients with EGFR-positive tumours and EGFR-negative tumours, respectively (P<0.05). This study shows that EGFR is frequently expressed in CUP. This finding may prompt clinical trials investigating EGFR inhibitors in this setting. In contrast, c-Kit expression and Her-2/neu overexpression occur infrequently in CUP. EGFR expression was correlated to tumour chemosensitivity.
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PMID:Carcinoma of an unknown primary: are EGF receptor, Her-2/neu, and c-Kit tyrosine kinases potential targets for therapy? 1787 36

Tyrosine kinase signaling is tightly controlled by negative feedback inhibitors including suppressors of cytokine signaling (SOCS). SOCS assemble as SH2 domain substrate recognition modules in ElonginB/C-cullin ubiquitin ligases. In accordance, SOCS4 reduces STAT3 signaling from EGFR through increased receptor degradation. Variable C-termini in SOCS4-SOCS7 exclude these family members from a SOCS2-type domain arrangement in which a strictly conserved C terminus determines domain packing. The structure of the SOCS4-ElonginC-ElonginB complex reveals a distinct SOCS structural class. The N-terminal ESS helix functionally replaces the CIS/SOCS1-SOCS3 family C terminus in a distinct SH2-SOCS box interface that facilitates further interdomain packing between the extended N- and C-terminal regions characteristic for this subfamily. Using peptide arrays and calorimetry the STAT3 site in EGFR (pY(1092)) was identified as a high affinity SOCS4 substrate (K(D) = 0.5 microM) revealing a mechanism for EGFR degradation. SOCS4 also bound JAK2 and KIT with low micromolar affinity, whereas SOCS2 was specific for GH-receptor.
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PMID:Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation. 1799 74


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