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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.
Highlights
Non-small-cell lung cancer (NSCLC) is the leading cause of death among cancers worldwide [1]
We recently discovered that the cancer-specific activation of FCH/F-BAR and Double SH3 Domain-Containing Protein (FCHSD2) downstream of extracellular signal-regulated kinases 1 and 2 (ERK1/2) contributes to adaptive clathrin-mediated endocytosis (CME) in NSCLC cells [15], in this case by suppressing epidermal growth factor receptor (EGFR) signaling
We have shown that FCHSD2 regulates endocytosis of transferrin receptor (TfnR) and EGFR and that it negatively regulates EGFR signaling from the cell surface [15]
Summary
Non-small-cell lung cancer (NSCLC) is the leading cause of death among cancers worldwide [1]. Transformed NSCLC cells surreptitiously multiply while undergoing generations of selected evolution to acquire the characteristics of an aggressive and metastatic tumor. In part, driven by altered signaling, often associated with activation of receptor tyrosine kinases (RTKs) [2,3,4]. The expression and activity of cell surface RTKs, in turn, is regulated predominantly through clathrin-mediated endocytosis (CME) [5,6,7], endosomal recycling, and/or degradation [8,9,10]. A link between endocytic trafficking and cancer progression has been suggested [8,11,12]. Few studies have focused on cancer-cell–specific alterations in endocytic trafficking
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