Role for ERK1/2-dependent activation of FCHSD2 in cancer cell-selective regulation of clathrinmediated endocytosis

Guan Yu Xiao, Aparna Mohanakrishnan, Sandra L. Schmid

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Clathrin-mediated endocytosis (CME) regulates the uptake of cellsurface receptors as well as their downstream signaling activities. We recently reported that signaling can reciprocally regulate CME in cancer cells and that this crosstalk can contribute to cancer progression. To further explore the nature and extent of the crosstalk between signaling and CME in cancer cell biology, we analyzed a panel of oncogenic signaling kinase inhibitors for their effects on CME across a panel of normal and cancerous cells. Inhibition of several kinases selectively affected CME in cancer cells, including inhibition of ERK1/2, which selectively inhibited CME by decreasing the rate of clathrin-coated pit (CCP) initiation. We identified an ERK1/2 substrate, the FCH/F-BAR and SH3 domain-containing protein FCHSD2, as being essential for the ERK1/2-dependent effects on CME and CCP initiation. Our data suggest that ERK1/2 phosphorylation activates FCHSD2 and regulates EGF receptor (EGFR) endocytic trafficking as well as downstream signaling activities. Loss of FCHSD2 activity in nonsmall cell lung cancer (NSCLC) cells leads to increased cell-surface expression and altered signaling downstream of EGFR, resulting in enhanced cell proliferation and migration. The expression level of FCHSD2 is positively correlated with higher NSCLC patient survival rates, suggesting that FCHSD2 can negatively affect cancer progression. These findings provide insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells.

Original languageEnglish
Pages (from-to)E9570-E9579
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
StatePublished - Oct 9 2018

Bibliographical note

Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.


  • Epidermal growth factor receptor
  • Nervous Wreck
  • Nonsmall cell lung cancer
  • Signal transduction

ASJC Scopus subject areas

  • General


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