Journal
DEVELOPMENTAL CELL
Volume 40, Issue 3, Pages 278-288Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2017.01.007
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Funding
- National Cancer Institute of the NIH [5P30CA142543]
- Texas Institute for Brain Injury and Repair (TIBIR)
- NIH [R01 GM73165, MH61345, GM42455]
- Taiwan National Science Council [103-2917-I-564-029]
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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 up regulation of dynamin-1 (Dyn1) and its activation through a positive feedback loop involving enhanced epidermal growth factor (EGF)-dependent Akt/GSK3 beta 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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