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- Title
FCHSD2 controls oncogenic ERK1/2 signaling outcome by regulating endocytic trafficking.
- Authors
Xiao, Guan-Yu; Schmid, Sandra L.
- 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. Clinically, NSCLC patients expressing high FCHSD2 exhibit elevated survival, whereas patients with high Rab7 expression display decreased survival rates. Our study provides new insight into the molecular nexus for crosstalk between oncogenic signaling and RTK trafficking that controls cancer progression. The evolution of transformed cancer cells into metastatic tumors is, in part, driven by altered intracellular signaling downstream of receptor tyrosine kinases. This study defines an endocytic trafficking pathway regulated by FCHSD2 and Rab7 that controls receptor tyrosine kinase expression and oncogenic signal transduction, opening the possibility of novel therapeutic strategies for cancer.
- Subjects
EPIDERMAL growth factor receptors; NON-small-cell lung carcinoma; RAS oncogenes; PROTEIN-tyrosine kinases; CANCER invasiveness
- Publication
PLoS Biology, 2020, Vol 18, Issue 7, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000778