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.
|State||Published - Jul 2020|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (NIH) (R01 GM45455 and GM73165 to SLS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank members of the Schmid lab for critically reading the manuscript, especially Marcel Mettlen for help in preparing illustrations and Kim Reed for technical assistance in plasmid preparation. We thank colleagues from the Department of Biophysics: Drs. Emiko Uchikawa and Xiaochen Bai for kindly providing recombinant human HGF. We acknowledge the UT Southwestern Tissue Resource, a shared resource at the Simmons Comprehensive Cancer Center, for assistance with immunohistochemistry data analysis and interpretation.
Copyright: © 2020 Xiao, Schmid. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ASJC Scopus subject areas
- Neuroscience (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Immunology and Microbiology (all)
- Agricultural and Biological Sciences (all)