Kinase Activity of RTKs Is Dispensable for Factor Independent Growth and Transformation of a Myeloid Cell Line 32D in the Presence of Cbl Mutants
| Autor: | Lara Tickenbrock, Marion Rensinghoff, Carsten Müller-Tidow, Rebekka Grundler, Wolfgang E. Berdel, Justus Duyster, Srinivasa Rao Bandi, Hubert Serve, Christian Brandts |
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| Rok vydání: | 2009 |
| Předmět: |
biology
Kinase media_common.quotation_subject Immunology Receptor Protein-Tyrosine Kinases Myeloid leukemia Cell Biology Hematology Biochemistry Receptor tyrosine kinase Cell biology hemic and lymphatic diseases biology.protein Kinase activity Signal transduction Internalization Tyrosine kinase media_common |
| Zdroj: | Blood. 114:3970-3970 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v114.22.3970.3970 |
| Popis: | Abstract 3970 Poster Board III-906 Purpose The Cbl proto-oncogene products have emerged as important components of the signal transduction cascades downstream of both non-receptor and receptor tyrosine kinases (RTKs). By regulation of receptor trafficking and degradation, they have been shown to tightly regulate the intensity and amplitude of RTK activation. c-Kit belongs to the family of the class-III RTKs and plays an important role in the pathogenesis of acute myeloid leukemia (AML). So far, very little is known about the role of c-Cbl mutants in the role of c-Kit signaling. Results We analyzed the interaction of c-Cbl with c-Kit and the functional relevance of this interaction in the IL-3-dependent murine myeloid progenitor cell line 32Dcl3. We recently identified the first c-Cbl mutation in human disease in an AML patient, named Cbl-R420Q. Co-expression of two different dominant negative mutants of c-Cbl (Cbl-R420Q or Cbl-70Z) with Kit induced cytokine-independent proliferation, survival and clonogenic growth. 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 RTKs, but independent of their kinase activity. Instead, transformation appeared to depend on Src family kinases (SFKs), as c-Cbl co-immunoprecipitated with SFKs and SFK inhibition abolished transformation. Conclusion Our results indicate that c-Cbl has an important role in c-Kit signal mitigation. They demonstrate that disturbed mechanisms of c-Kit internalization have important implications for its transforming potential, possibly in the development of AML. Furthermore, these findings may explain primary resistance to tyrosine kinase inhibitors targeted at RTKs. Disclosures: No relevant conflicts of interest to declare. |
| Databáze: | OpenAIRE |
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