Crosstalk between CLCb/Dyn1-Mediated Adaptive Clathrin-Mediated Endocytosis and Epidermal Growth Factor Receptor Signaling Increases Metastasis

Publication date: 6 February 2017
Source:Developmental Cell, Volume 40, Issue 3
Author(s): 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.

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Teaser

Signaling downstream of receptor tyrosine kinases is regulated by their trafficking. Chen et al. show that isoform-specific upregulation of clathrin light chain b and dynamin-1 in cancer cells, coupled to reciprocal crosstalk with Akt/GSK3β signaling, leads to adaptive clathrin-mediated endocytosis that alters EGFR trafficking and signaling and increases metastasis.


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