FCHSD2 controls oncogenic ERK1/2 signaling outcome by regulating endocytic trafficking.

PLoS Biology
Guan-Yu Xiao, Sandra L Schmid

Abstract

The evolution of transformed cancer cells into metastatic tumors is, in part, driven by altered intracellular signaling downstream of receptor tyrosine kinases (RTKs). The surface levels and activity of RTKs are governed mainly through clathrin-mediated endocytosis (CME), endosomal recycling, or degradation. In turn, oncogenic signaling downstream of RTKs can reciprocally regulate endocytic trafficking by creating feedback loops in cells to enhance tumor progression. We previously showed that FCH/F-BAR and Double SH3 Domain-Containing Protein (FCHSD2) has a cancer-cell specific function in regulating CME in non-small-cell lung cancer (NSCLC) cells. Here, we report that FCHSD2 loss impacts recycling of the RTKs, epidermal growth factor receptor (EGFR) and proto-oncogene c-Met (MET), and shunts their trafficking into late endosomes and lysosomal degradation. Notably, FCHSD2 depletion results in the nuclear translocation of active extracellular signal-regulated kinase 1 and 2 (ERK1/2), leading to enhanced transcription and up-regulation of EGFR and MET. The small GTPase, Ras-related protein Rab-7A (Rab7), is essential for the FCHSD2 depletion-induced effects. Correspondingly, FCHSD2 loss correlates to higher tumor grades of NSCLC....Continue Reading

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Citations

Feb 20, 2021·Annual Review of Biochemistry·Mark von Zastrow, Alexander Sorkin
Jun 19, 2021·Frontiers in Cell and Developmental Biology·Hongyuan JinHangyu Li
Jul 30, 2021·ELife·Steven J Del SignoreAvital Adah Rodal

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Methods Mentioned

BETA
nuclear translocation
GTPases
nucleotide
GTPase
confocal microscopy
reverse transcription PCR
transfection
Assay

Software Mentioned

GraphPad Prism
IHC Profiler
ImageJ

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