Our attempt to explore the molecular mechanism underlying HHD indicates a complex puzzle in which multi-hit combinations of altered signal pathways may explain the wide spectrum of defects in HHD.
Integrated pathways are believed to determine hematopoietic cell fate and/or neoplastic transformation. Notch signaling has been shown to regulate T-cell differentiation and leukemogenesis. However, specific target genes and molecular partners are not fully elucidated. We show that Notch3 activation sustains aberrant SCL / Tal1
Notch3 and pT alpha signaling events are essential for T-cell leukemogenesis and characterize murine and human T-cell acute lymphoblastic leukemia. Genetic ablation of pT alpha expression in Notch3 transgenic mice abrogates tumor development, indicating that pT alpha signaling is crucial to the Notch3-mediated leukemogenesis. Here we report a novel direct interaction between Notch3 and pT alpha. This interaction leads to the recruitment and persistence of the E3 ligase protein c-Cbl to the lipid rafts in Notch3-IC transgenic thymocytes. Conversely, deletion of pT alpha in Notch3 transgenic mice leads to cytoplasmic retention of c-Cbl that targets Notch3 protein to the proteasomal-degradative pathway. It appears that protein kinase C theta (PKC theta), by regulating tyrosine and serine phosphorylation of Cbl, is able to control its function. We report here that the increased Notch3-IC degradation correlates with higher levels of c-Cbl tyrosine phosphorylation in Notch3-IC/pT alpha(-/-) double-mutant thymocytes, which also display a decreased PKC theta activity. Our data indicate that pT alpha/pre-T-cell receptor is able to regulate the different subcellular localization of c-Cbl and, by regulating PKC theta activity, is also able to influence its ubiquitin ligase activity upon Notch3 protein. Oncogene (2010) 29, 1463-1474; doi:10.1038/onc.2009.446; published online 7 December 200
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