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)

Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCtheta in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins - including JAK1 and EPHA4 - did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.
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PMID:KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance. 1745 78

Primary sarcomas of the great vessels are very rare neoplasms and only a few cases have been reported. They are divided into the two broad categories of intimal or luminal and mural sarcomas. We analysed eight advanced high-grade sarcomas originating from major vessels (seven intimal and one mural sarcoma) by means of immunohistochemistry and FISH analysis for PDGFRA, PDGFRB, EGFR and KIT receptor tyrosine kinases (RTKs), together with immunoprecipitation/western blotting, sequencing of the corresponding genes, and the search for cognate ligands. The intimal sarcomas showed a wide spectrum of morphologies and immunophenotypes, whereas the mural sarcoma had common leiomyosarcomatous features. Regardless of their category, all of the cases had a PDGFRA-deregulated cytogenetic profile mainly consisting of an amplification cluster; five were also polysomic for PDGFRB, whereas three showed disomy. Six cases had a deregulated EGFR gene, and c-Kit gene status was similar to that of PDGFRA. In one case, biochemical analysis revealed the presence of activated and highly expressed PDGFRA, PDGFRB and EGFR, whereas KIT was expressed at reference level. Sequencing of the corresponding genes revealed no activating mutations in any of the analysed receptors. The cognate ligands were detected in all cases. In predictive terms, the evidence of gene amplification/high polysomy of several RTKs, together with PDGFRA, PDGFRB and EGFR expression and phosphorylation, suggests that these tumours may be sensitive to RTK-inhibiting treatments.
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PMID:Analysis of potential receptor tyrosine kinase targets in intimal and mural sarcomas. 1747 66

Fluorescence in situ hybridization (FISH) and reverse-transcription polymerase chain reaction (RT-PCR) detected the ETV6-PDGFRB fusion in a patient with chronic myelomonocytic leukemia characterized by bone marrow and peripheral blood eosinophilia and a four-way t(1;12;5;12)(p36;p13;q33;q24) on bone marrow cells. The patient consequently underwent imatinib mesylate therapy and achieved hematologic, FISH, and molecular remission. The FICTION technique (fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms) demonstrated that eosinophils and CD13(+) and CD14(+) cells belong to the neoplastic clone bearing the ETV6-PDGFRB rearrangement. Molecular cytogenetics is the most reliable approach to detect the involvement of promiscuous genes, such as PDGFRB, and to properly classify genetic entities for which targeted therapies are available. Assessment of cell lineages harboring the genomic lesion may contribute in the understanding of leukemogenic pathways.
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PMID:Molecular cytogenetic findings in a four-way t(1;12;5;12)(p36;p13;q33;q24) underlying the ETV6-PDGFRB fusion gene in chronic myelomonocytic leukemia. 1757 67

The commonly deleted region (CDR) for the 5q- syndrome has been identified as a 1.5-megabase interval on human chromosome 5q32. We studied, by real-time reverse-transcription (RT)-PCR, the expression of 33 genes within the CDR that are known to be expressed in CD34+ hematopoietic stem cells. Genes in the 5q- samples that showed the most pronounced decrease in expression compared to non-5q- samples were: solute carrier family 36, member 1 (SLC36A1; 89% downregulated), Ras-GTPase-activating protein SH3 domain-binding (G3BP; 79%), antioxidant protein 1 (ATOX1; 76%), colony-stimulating factor-1 receptor precursor (CSF1R; 76%), ribosomal protein S14 (RPS14; 74%), platelet-derived growth factor receptor-beta (PDGFRB; 73%), Nef-associated factor 1 (TNIP1; 72%), secreted protein, acidic and rich in cysteine (SPARC; 71%), annexin VI (ANAX6; 69%), NSDT (66%) and TIGD (60%). We further studied the hematopoietic system in SPARC-null mice. These mice showed significantly lower platelet counts compared to wild-type animals (P=0.008). Although hemoglobin, hematocrit and mean corpuscular volume (MCV) were lower in mice lacking SPARC, differences were not statistically significant. SPARC-null mice showed a significantly impaired ability to form erythroid burst-forming units (BFU-E). However, no significant differences were found in the formation of erythroid colony-forming units (CFU-E), granulocyte/monocyte colony-forming units (CFU-GM) or megakaryocyte colony-forming units (CFU-Mk) in these animals. We conclude that many of the genes within the CDR associated with the 5q- syndrome exhibit significantly decreased expression and that SPARC, as a potential tumor suppressor gene, may play a role in the pathogenesis of this disease.
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PMID:Common deleted genes in the 5q- syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice. 1762 8

We report a case of chronic eosinophilic leukemia (CEL), demonstrating for the first time: (i) the association of CEL with the 5'KIAA1509/3'PDGFRB fusion gene as a consequence of a t(5;14)(q33;q32); (ii) the molecular detection of this rearrangement in an extramedullary site; (iii) the cloning and sequencing of the KIAA1509 and PDGFRB genomic breakpoints. The 5'KIAA1509/3'PDGFRB fusion gene is predicted to encode a protein of 2059 amino acids. The genomic breakpoints were localized inside KIAA1509 intron 11 and PDGFRB intron 10. Sequence analysis in correspondence with these breakpoints revealed the presence of repetitive DNA, such Alu elements, which could promote chromosomal rearrangements.
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PMID:Extramedullary molecular evidence of the 5'KIAA1509/3'PDGFRB fusion gene in chronic eosinophilic leukemia. 1768 99

Sunitinib (SU11248) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis, including vascular endothelial growth factor (VEGF) receptors 1, 2, 3, and platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB). Because angiogenesis is necessary for the growth and metastasis of solid tumours, and VEGF is believed to have a pivotal role in that process, SUNITINIB treatment may have broad-spectrum clinical utility. In the present article, we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types: relapsed diffuse large cell lymphoma, malignant pleural mesothelioma, locally advanced or metastatic cervical cancer and recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
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PMID:Phase II testing of sunitinib: the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND.182-185. 1771 Feb 8

Among patients with hypereosinophilia, a myeloproliferative variant is recognized. In many of these patients a diagnosis of eosinophilic leukemia can be made. The molecular mechanism is often a fusion gene, incorporating part of PDGFRA or PDGFRB, encoding anaberrant tyrosine kinase. Prompt diagnosis of such cases is important since specific tyrosine kinase inhibitor therapy is indicated.
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PMID:Chronic eosinophilic leukemias and the myeloproliferative variant of the hypereosinophilic syndrome. 1786 55

The Philadelphia-negative chronic myeloproliferative diseases (CMPD) are very complex and heterogeneous disorders. They are represented by polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), CMPD/unclassifiable (CMPD-U), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) according to the WHO classification. Before, diagnostics were mainly focused on clinical and morphological aspects, but in recent years cytogenetics and fluorescence in situ hybridization (FISH) found entrance in routine schedules as chromosomal abnormalities are relevant for prognosis and classification. Recently, there is rapid progress in the field of molecular characterization: the JAK2V617F mutation which shows a high incidence in PV, CIMF, and ET already plays a central role and will probably soon be included in follow-up procedures. Due to the detection of mutations in exon 12 of the JAK2 gene or mutations in the MPL gene the variety of activating mutations in the CMPD is still increasing. In CEL/HES the detection of the FIP1L1-PDGFRA fusion gene and overexpression of PDGFRA and PDGFRB led to targeted therapy with tyrosine kinase inhibitors. Thus, diagnostics in the CMPD transform toward a multimodal diagnostic concept based on a combination of methods - cyto-/histomorphology, cytogenetics, and individual molecular methods which can be included in a diagnostic algorithm.
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PMID:[Diagnostic algorithm in chronic myeloproliferative diseases (CMPD)]. 1787 17

Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors alpha and beta as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor alpha and 13 cases (59%) showing high staining scores for PDGF receptor beta. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases). PDGFRB amplification status and PDGF receptor beta protein expression scores were significantly correlated (P=0.01, Spearman). Expression status of PDGF receptor alpha or PDGF receptor beta was not significantly associated with progression-free survival. To conclude, expression and amplification of PDGF receptors, particularly PDGF receptor beta, are frequent in choroid plexus carcinomas, providing a first rationale for the development of treatments targeting PDGF receptor signaling in these rare malignant pediatric tumors.
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PMID:Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas. 1815 90

We report a considerable number of cells in the ventricular and the subventricular zones (SVZ) of newborn mice to stain positive for the PDGF beta-receptor (PDGFRB). Many of them also stained for nestin and/or GFAP but less frequently for the neuroblast marker doublecortin and for the mitotic marker Ki-67. The SVZ of mice with nestin-Cre conditional deletion of PDGFRB expressed the receptor only on blood vessels and was devoid of any morphological abnormality. PDGFRB(-/-) neurospheres showed a higher rate of apoptosis without any significant decrease in proliferation. They demonstrated reduced capacities of migration and neuronal differentiation in response to not only PDGF-BB but also bFGF. Furthermore, the PDGFR kinase inhibitor STI571 blocked the effects of bFGF in control neurosphere cultures. bFGF increased the activity of the PDGFRB promoter as well as the expression and phosphorylation of PDGFRB. These results suggest the presence of the signaling convergence between PDGF and FGF. PDGFRB is needed for survival, and the effects of bFGF in migration and neural differentiation of the cells may be potentiated by induction of PDGFRB.
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PMID:Characterization of neuroprogenitor cells expressing the PDGF beta-receptor within the subventricular zone of postnatal mice. 1824 33


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