| pubmed-article:19734451 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:19734451 | lifeskim:mentions | umls-concept:C0024899 | lld:lifeskim |
| pubmed-article:19734451 | lifeskim:mentions | umls-concept:C0027022 | lld:lifeskim |
| pubmed-article:19734451 | lifeskim:mentions | umls-concept:C0023175 | lld:lifeskim |
| pubmed-article:19734451 | lifeskim:mentions | umls-concept:C0596988 | lld:lifeskim |
| pubmed-article:19734451 | lifeskim:mentions | umls-concept:C0205246 | lld:lifeskim |
| pubmed-article:19734451 | pubmed:issue | 19 | lld:pubmed |
| pubmed-article:19734451 | pubmed:dateCreated | 2009-11-6 | lld:pubmed |
| pubmed-article:19734451 | pubmed:abstractText | Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold. We recently identified the first c-Cbl mutation in human disease in an acute myeloid leukemia patient, called Cbl-R420Q. Here we analyzed the role of Cbl mutants on Kit-mediated transformation. Coexpression of Cbl-R420Q or Cbl-70Z with Kit induced cytokine-independent proliferation, survival, and clonogenic growth. Primary murine bone marrow retrovirally transduced with c-Cbl mutants and transplanted into mice led to a generalized mastocytosis, a myeloproliferative disease, and myeloid leukemia. Overexpression of these Cbl mutants inhibited stem cell factor (SCF)-induced ubiquitination and internalization of Kit. Both Cbl mutants enhanced the basal activation of Akt and prolonged the ligand-dependent activation. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on receptor tyrosine kinases, but independent of their kinase activity. Instead, transformation depends on the Src family kinase Fyn, as c-Cbl coimmunoprecipitated with Fyn and inhibition abolished transformation. These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases. | lld:pubmed |
| pubmed-article:19734451 | pubmed:language | eng | lld:pubmed |
| pubmed-article:19734451 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19734451 | pubmed:citationSubset | AIM | lld:pubmed |
| pubmed-article:19734451 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19734451 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19734451 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19734451 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19734451 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19734451 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:19734451 | pubmed:month | Nov | lld:pubmed |
| pubmed-article:19734451 | pubmed:issn | 1528-0020 | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:BerdelWolfgan... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:DuysterJustus... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:ServeHubertH | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:TickenbrockLa... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:Müller-TidowC... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:KöhlerGabriel... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:SarginBülentB | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:GrundlerRebek... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:BrandtsChrist... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:RensinghoffMa... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:BandiSrinivas... | lld:pubmed |
| pubmed-article:19734451 | pubmed:author | pubmed-author:Study... | lld:pubmed |
| pubmed-article:19734451 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:19734451 | pubmed:day | 5 | lld:pubmed |
| pubmed-article:19734451 | pubmed:volume | 114 | lld:pubmed |
| pubmed-article:19734451 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:19734451 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:19734451 | pubmed:pagination | 4197-208 | lld:pubmed |
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| pubmed-article:19734451 | pubmed:meshHeading | pubmed-meshheading:19734451... | lld:pubmed |
| pubmed-article:19734451 | pubmed:meshHeading | pubmed-meshheading:19734451... | lld:pubmed |
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| pubmed-article:19734451 | pubmed:meshHeading | pubmed-meshheading:19734451... | lld:pubmed |
| pubmed-article:19734451 | pubmed:year | 2009 | lld:pubmed |
| pubmed-article:19734451 | pubmed:articleTitle | E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease. | lld:pubmed |
| pubmed-article:19734451 | pubmed:affiliation | Department of Medicine, Hematology and Oncology and the Interdisciplinary Center for Clinical Research, University Hospital Muenster, Muenster, Germany. | lld:pubmed |
| pubmed-article:19734451 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:19734451 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
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