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

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.

Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery

“…Nwk is a conserved membrane-remodeling protein that physically interacts with components of the canonical clathrin-associated endocytic machinery ( Almeida-Souza et al, 2018 ; Del Signore et al, 2021 ; O’Connor-Giles et al, 2008 ; Rodal et al, 2008 ; Xiao et al, 2018 ; Xiao and Schmid, 2020 ). At Drosophila synapses, this machinery controls synaptic vesicle recycling, synaptic transmission, and growth factor receptor trafficking ( Deshpande and Rodal, 2015 ; Kaempf and Maritzen, 2017 ).…”

Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery

“…Nwk is a conserved membrane-remodeling protein that physically interacts with components of the canonical clathrin-mediated endocytic machinery (Almeida-Souza et al, 2018; Del Signore et al, 2021; O’Connor-Giles et al, 2008; Rodal et al, 2008; Xiao et al, 2018; Xiao and Schmid, 2020). At Drosophila synapses, this machinery controls synaptic vesicle recycling, synaptic transmission, and growth factor receptor trafficking (Kaempf and Maritzen, 2017).…”

“…Clathrin localizes directly to endosomes, where it regulates endosomal cargo sorting and intralumenal vesicle formation (Raiborg et al, 2001; Raiborg et al, 2006; Sachse et al, 2002; Shi et al, 2009; Wenzel et al, 2018). Further, the mammalian Nwk homolog FCHSD2, in addition to its role at the internalization step of endocytosis (Almeida-Souza et al, 2018; Xiao et al, 2018), suppresses recycling and lysosomal degradation of signaling receptors (Xiao and Schmid, 2020). The extreme density of endocytic machinery at synaptic membranes makes it difficult to detect a small endosomally localized fraction of this machinery, though Nwk does exhibit partial co-localization with Rab11 (Rodal et al, 2008).…”

Rab GTPases: Central Coordinators of Membrane Trafficking in Cancer

“…Rab7 is an early-induced melanoma driver (Alonso-Curbelo et al, 2014). In addition, lung cancer and gastric cancer patients with high Rab7 expression show decreased survival rates (Liu et al, 2020;Xiao and Schmid, 2020). High Rab10 expression levels are associated with poor prognosis in HCC patients (Wang W. et al, 2017).…”