Source:http://linkedlifedata.com/resource/pubmed/id/19734451
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
19
|
| pubmed:dateCreated |
2009-11-6
|
| 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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CBL protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cbl protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-cbl,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-kit
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Nov
|
| pubmed:issn |
1528-0020
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| pubmed:author |
pubmed-author:BandiSrinivasa RaoSR,
pubmed-author:BerdelWolfgang EWE,
pubmed-author:BrandtsChristianC,
pubmed-author:DuysterJustusJ,
pubmed-author:GrundlerRebekkaR,
pubmed-author:KöhlerGabrieleG,
pubmed-author:Müller-TidowCarstenC,
pubmed-author:RensinghoffMarionM,
pubmed-author:SarginBülentB,
pubmed-author:ServeHubertH,
pubmed-author:Study Alliance Leukemias,
pubmed-author:TickenbrockLaraL
|
| pubmed:issnType |
Electronic
|
| pubmed:day |
5
|
| pubmed:volume |
114
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
4197-208
|
| pubmed:meshHeading |
pubmed-meshheading:19734451-Animals,
pubmed-meshheading:19734451-Bone Marrow Transplantation,
pubmed-meshheading:19734451-COS Cells,
pubmed-meshheading:19734451-Cell Transformation, Neoplastic,
pubmed-meshheading:19734451-Cercopithecus aethiops,
pubmed-meshheading:19734451-Disease Models, Animal,
pubmed-meshheading:19734451-Female,
pubmed-meshheading:19734451-Humans,
pubmed-meshheading:19734451-Ligands,
pubmed-meshheading:19734451-Mastocytosis,
pubmed-meshheading:19734451-Mice,
pubmed-meshheading:19734451-Mice, Inbred BALB C,
pubmed-meshheading:19734451-Mutagenesis, Site-Directed,
pubmed-meshheading:19734451-Mutation,
pubmed-meshheading:19734451-Myeloproliferative Disorders,
pubmed-meshheading:19734451-Proto-Oncogene Proteins c-cbl,
pubmed-meshheading:19734451-Proto-Oncogene Proteins c-kit,
pubmed-meshheading:19734451-Signal Transduction,
pubmed-meshheading:19734451-Ubiquitination
|
| pubmed:year |
2009
|
| pubmed:articleTitle |
E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease.
|
| pubmed:affiliation |
Department of Medicine, Hematology and Oncology and the Interdisciplinary Center for Clinical Research, University Hospital Muenster, Muenster, Germany.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|