CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling
CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling
复制标题
DOI：
10.15252/embj.201899395
复制
发表时间：
2018-10-15
期刊：
影响因子：
11.4
通讯作者：
Hui, Kam Man
中科院分区：
文献类型：
--
作者：
Chen, Jianxiang;Rajasekaran, Muthukumar;Hui, Kam Man
细胞分裂失控是癌症的一个标志。Wnt组分的解除调控通过多种机制与细胞的异常分裂联系在一起，包括Wnt介导的蛋白质信号稳定，这在有丝分裂中被显著观察到。对Wnt组分的分析显示，B细胞CLL/淋巴瘤9(BCL9)在维持有丝分裂Wnt信号以促进癌细胞的精确分裂和生长方面发挥了意想不到的作用。有丝分裂相互作用组分析表明，BCL9通过与Cathrin和Wnt破坏复合体中的组分相互作用来抑制Cathrin介导的LRP6信号体成分的降解，这一作用进一步受CDK1驱动的BCL9N末端的磷酸化控制，尤其是T172。有趣的是，T172的磷酸化与癌症患者的预后相关，并在肿瘤中丰富。因此，我们的结果揭示了BCL9在控制有丝分裂Wnt信号以促进细胞分裂和生长方面的新作用。
Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt destruction complex; this function was further controlled by CDK1-driven phosphorylation of BCL9N-terminal, especially T172. Interestingly, T172 phosphorylation was correlated with cancer patient prognosis and enriched in tumours. Thus, our results revealed a novel role of BCL9 in controlling mitotic Wnt signalling to promote cell division and growth.