c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor
c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor
复制标题
DOI：
10.1016/j.molcel.2012.12.002
复制
发表时间：
2013-02-07
期刊：
影响因子：
16
通讯作者：
Chen, Ye-Guang
中科院分区：
文献类型：
--
作者：
Zuo, Wei;Huang, Fei;Chen, Ye-Guang
转化生长因子β（TGF-β）是多种类型细胞中的有效抗增殖因子。TGF-β信号的失调与许多癌症的发展有关，包括白血病，尽管分子机制在很大程度上尚不清楚。在这里，我们发现Casitas B系淋巴瘤（c-Cbl），一种已知的编码泛素E3连接酶的原癌基因，通过neddylating和稳定II型受体（T β RII）促进TGF-β信号传导。c-Cbl的敲除降低了T β RII蛋白水平并使造血干细胞或祖细胞对TGF-β刺激脱敏，而c-Cbl的过表达稳定了T β RII并使白血病细胞对TGF-β敏感。c-Cbl将神经前体细胞表达的发育下调蛋白8（NEDD 8）（一种泛素样蛋白）与T β RII在Lys 556和Lys 567处结合。TbetaRII的Neddylation促进其内吞到EEA 1阳性早期内体，同时阻止其内吞到小窝蛋白阳性隔室，因此抑制TbetaRII泛素化和降解。我们还从白血病患者中发现了一个neddylation活性缺陷的c-Cbl突变，这意味着异常的T β RII neddylation和白血病发展之间存在联系。
Transforming growth factor beta (TGF-beta) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-beta signaling is associated with the development of many cancers, including leukemia, though the molecular mechanisms are largely unclear. Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-beta signaling by neddylating and stabilizing the type II receptor (T beta RII). Knockout of c-Cbl decreases the T beta RII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-beta stimulation, while c-Cbl overexpression stabilizes T beta RII and sensitizes leukemia cells to TGF-beta. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to T beta RII at Lys556 and Lys567. Neddylation of T beta RII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting T beta RII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant T beta RII neddylation and leukemia development.