CDK1-Mediated BCL9 Phosphorylation Inhibits Clathrin to Promote Mitotic Wnt Signalling

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 stabilization 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 BCL9 N-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.

细胞不受控分裂是癌症的标志性特征之一。Wnt信号通路组分的失调已被证实可通过多种机制诱发异常细胞分裂，其中包括Wnt介导的蛋白质信号稳定效应，该效应在有丝分裂过程中已被显著观测到。针对Wnt信号通路组分的分析揭示了B细胞慢性淋巴细胞白血病/淋巴瘤9（B-cell CLL/lymphoma 9，BCL9）此前未被认知的功能：其可维持有丝分裂阶段的Wnt信号转导，进而促进癌细胞的精准分裂与增殖。有丝分裂互作组分析进一步揭示了BCL9的具体作用机制：它可通过与网格蛋白（Clathrin）及Wnt降解复合体的组分相结合，抑制网格蛋白介导的低密度脂蛋白受体相关蛋白6（LRP6）信号小体组分降解。该功能的发挥进一步受细胞周期蛋白依赖性激酶1（CDK1）介导的BCL9 N端磷酸化调控，尤以苏氨酸172（T172）位点的磷酸化作用最为关键。值得注意的是，T172位点的磷酸化水平与癌症患者的预后密切相关，且在肿瘤组织中呈现富集状态。综上，本研究结果揭示了BCL9在调控有丝分裂Wnt信号转导以促进细胞分裂与增殖方面的全新功能。