Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia
Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia
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DOI：
10.1038/onc.2009.446
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发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Screpanti, I.
中科院分区：
文献类型：
--
作者：
Checquolo, S.;Palermo, R.;Screpanti, I.
Notch 3和pT α信号传导事件是T细胞白血病发生所必需的，并表征鼠和人T细胞急性淋巴细胞白血病。Notch 3转基因小鼠中pT α表达的基因消除消除了肿瘤的发展，表明pT α信号传导对Notch 3介导的白血病发生至关重要。在这里，我们报告了一种新的Notch 3和pT α之间的直接相互作用。这种相互作用导致E3连接酶蛋白c-Cbl在Notch 3-IC转基因胸腺细胞中的脂筏的募集和持续存在。相反，Notch 3转基因小鼠中pT α的缺失导致c-Cbl的细胞质保留，c-Cbl将Notch 3蛋白靶向蛋白酶体降解途径。蛋白激酶C θ（PKC θ）通过调节Cbl的酪氨酸和丝氨酸磷酸化，似乎能够控制其功能。我们在此报道，Notch 3-IC降解的增加与Notch 3-IC/pT α（-/-）双突变胸腺细胞中c-Cbl酪氨酸磷酸化水平的升高相关，这也显示出PKC θ活性的降低。我们的数据表明，pT α/前T细胞受体能够调节c-Cbl的不同亚细胞定位，并且通过调节PKC θ活性，也能够影响其对Notch 3蛋白的泛素连接酶活性。Oncogene（2010）29，1463-1474; doi：10.1038/onc.2009.446; 2009年12月7日在线发表
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