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 2009

Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia / Checquolo, Saula; Palermo, Rocco; Cialfi, Samantha; Ferrara, Grazia; C., Oliviero; Talora, Claudio; Bellavia, Diana; A., Giovenco; Grazioli, Paola; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 29:10(2010), pp. 1463-1474. [10.1038/onc.2009.446]

Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia

CHECQUOLO, Saula;PALERMO, ROCCO;CIALFI, Samantha;FERRARA, GRAZIA;TALORA, Claudio;BELLAVIA, Diana;GRAZIOLI, PAOLA;FRATI, Luigi;GULINO, Alberto;SCREPANTI, Isabella
2010

Abstract

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 2009
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/145820
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