Running Title: Role of Cbl mutations in myeloid transformation
作者： Lara Tickenbrock , Ivan Dikic , Steffen Koschmieder , Bülent Sargin , Benjamin August
DOI:
关键词: Signal transduction 、 Genetics 、 Receptor tyrosine kinase 、 Ubiquitin 、 Myeloid 、 Phosphorylation 、 Cell biology 、 Tyrosine 、 Biology 、 Internalization 、 Myeloid leukemia
摘要: Abstract In acute myeloid leukemia (AML), mutational activation of the receptor tyrosine kinase (RTK) Flt3 is frequently involved in leukemic transformation. However, little known about a possible role highly expressed wild-type AML. The proto-oncogene c-Cbl an important regulator RTK signaling, acting through its ubiquitin ligase activity and as platform for several signaling adaptor molecules. Here, we analyzed signal transduction C-Cbl physically interacted with was phosphorylated presence Flt3-ligand (FL). Overexpression dominant negative form (Cbl-70Z) inhibited FL-induced ubiquitylation internalization, indicating involvement signaling. DNA sequencing AML bone marrow revealed case point mutation (Cbl-R420Q). Cbl-R420Q internalization ubiquitylation. Co-expression or Cbl-70Z induced cytokine-independent growth survival 32Dcl3 cells absence FL. Also, mutant Cbl proteins altered amplitude duration Flt3-dependent events. Our results indicate modulation. data suggest novel mechanism transformation by inactivation regulators. From bloodjournal.hematologylibrary.org guest on June 6, 2013. For personal use only.
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