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Crosstalk between CLCb/Dyn1-Mediated Adaptive Clathrin-Mediated Endocytosis and Epidermal Growth Factor Receptor Signaling Increases Metastasis
Developmental Cell ( IF 10.7 ) Pub Date : 2017-02-06 , DOI: 10.1016/j.devcel.2017.01.007
Ping-Hung Chen , Nawal Bendris , Yi-Jing Hsiao , Carlos R. Reis , Marcel Mettlen , Hsuan-Yu Chen , Sung-Liang Yu , Sandra L. Schmid

Signaling receptors are internalized and regulated by clathrin-mediated endocytosis (CME). Two clathrin light chain isoforms, CLCa and CLCb, are integral components of the endocytic machinery whose differential functions remain unknown. We report that CLCb is specifically upregulated in non-small-cell lung cancer (NSCLC) cells and is associated with poor patient prognosis. Engineered single CLCb-expressing NSCLC cells, as well as “switched” cells that predominantly express CLCb, exhibit increased rates of CME and altered clathrin-coated pit dynamics. This “adaptive CME” resulted from upregulation of dynamin-1 (Dyn1) and its activation through a positive feedback loop involving enhanced epidermal growth factor (EGF)-dependent Akt/GSK3β phosphorylation. CLCb/Dyn1-dependent adaptive CME selectively altered EGF receptor trafficking, enhanced cell migration in vitro, and increased the metastatic efficiency of NSCLC cells in vivo. We define molecular mechanisms for adaptive CME in cancer cells and a role for the reciprocal crosstalk between signaling and CME in cancer progression.



中文翻译:


CLCb/Dyn1 介导的适应性网格蛋白介导的内吞作用与表皮生长因子受体信号传导之间的串扰增加了转移



信号受体通过网格蛋白介导的内吞作用 (CME) 内化和调节。两种网格蛋白轻链亚型 CLCa 和 CLCb 是内吞机制的组成部分,其差异功能仍不清楚。我们报告说,CLCb 在非小细胞肺癌 (NSCLC) 细胞中特异性上调,并且与患者预后不良相关。工程化的单个表达 CLCb 的 NSCLC 细胞以及主要表达 CLCb 的“转换”细胞,表现出 CME 发生率增加和网格蛋白包被的小坑动态改变。这种“适应性 CME”是由于 dynamin-1 (Dyn1) 上调及其通过正反馈环路激活所致,该正反馈环路涉及增强的表皮生长因子 (EGF) 依赖性 Akt/GSK3β 磷酸化。 CLCb/Dyn1 依赖性适应性 CME 选择性改变 EGF 受体运输,增强体外细胞迁移,并提高 NSCLC 细胞体内转移效率。我们定义了癌细胞中适应性 CME 的分子机制,以及信号传导和 CME 之间的相互串扰在癌症进展中的作用。

更新日期:2017-02-06
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