Abstract
Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signaling pathways. Internalization and degradation of EGFR after ligand binding limits the intensity of proliferative signaling, thereby helping to maintain cell integrity. In cancer cells, deregulation of EGFR trafficking has a variety of effects on tumor progression. Here we report that sortilin is a key regulator of EGFR internalization. Loss of sortilin in tumor cells promoted cell proliferation by sustaining EGFR signaling at the cell surface, ultimately accelerating tumor growth. In lung cancer patients, sortilin expression decreased with increased pathologic grade, and expression of sortilin was strongly correlated with survival, especially in patients with high EGFR expression. Sortilin is therefore a regulator of EGFR intracellular trafficking that promotes receptor internalization and limits signaling, which in turn impacts tumor growth.
Highlights
Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signaling pathways
Because multiple facets of EGFR trafficking remain unresolved[19], and EGFR internalization represents a crucial step for signal termination, we investigated the role of sortilin[20,21,22] in EGFR regulation following EGF-induced EGFR internalization
Because EGFR is not present in exosomes derived from sortilin-depleted cells, we focused on the function of sortilin in EGFR intracellular trafficking
Summary
Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signaling pathways. Sortilin is a regulator of EGFR intracellular trafficking that promotes receptor internalization and limits signaling, which in turn impacts tumor growth. The rapid internalization and degradation of the EGFR are under tight spatiotemporal control to limit cell proliferation promoted by mitogen activated protein kinases (MAPKs)[7,8,9]. This negative feedback mechanism, governed by ligand-induced lysosomal degradation of EGFR, ensures signal termination and counteracts the oncogenic and transforming role of EGFR10–12. Sortilin expression represents a favorable prognostic marker in lung adenocarcinoma patients
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