Mechanism of p38 MAPK–induced EGFR endocytosis and its crosstalk with ligand-induced pathways

Abstract

Ligand binding triggers clathrin-mediated and, at high ligand concentrations, clathrin-independent endocytosis of EGFR. Clathrin-mediated endocytosis (CME) of EGFR is also induced by stimuli activating p38 MAPK. Mechanisms of both ligand- and p38-induced endocytosis are not fully understood, and how these pathways intermingle when concurrently activated remains unknown. Here we dissect the mechanisms of p38-induced endocytosis using a pH-sensitive model of endogenous EGFR, which is extracellularly tagged with a fluorogen-activating protein, and propose a unifying model of the crosstalk between multiple EGFR endocytosis pathways. We found that a new locus of p38-dependent phosphorylation in EGFR is essential for the receptor dileucine motif interaction with the σ2 subunit of clathrin adaptor AP2 and concomitant receptor internalization. p38-dependent endocytosis of EGFR induced by cytokines was additive to CME induced by picomolar EGF concentrations but constrained to internalizing ligand-free EGFRs due to Grb2 recruitment by ligand-activated EGFRs. Nanomolar EGF concentrations rerouted EGFR from CME to clathrin-independent endocytosis, primarily by diminishing p38-dependent endocytosis.

The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways

“…Moreover, unlike ligand-dependent EGFR phosphorylation, p38-dependent EGFR phosphorylation did not trigger downstream signaling responses through ERK1/2. p38-dependent EGFR phosphorylation is associated with clathrin-mediated EGFR endocytosis (28,(79)(80)(81), and the endocytosed receptor does not contribute to ERK1/2 signaling (82), suggesting therefore that p38 inhibition may retain EGFR on the plasma membrane where it can more effectively contribute to ERK1/2 signaling during candidalysin stimulation.…”

EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin

“…The c-Cbl adaptor is important in EGFR trafficking and regulation (59, 60); notably, ubiquitination of EGFR by c-Cbl is implicated in clathrin-independent endocytosis of EGFR and regulation of EGFR signaling (61). Additionally, though the p38 MAPK pathway is pivotal in mediating EGFR endocytosis (62), little is known about the role of p38 in mediating EGFR trafficking in response to infection. It is likely that the complex dynamics of EGFR trafficking during fungal infection plays a significant role in EGFR signaling and the OEC immune response.…”

Time-resolved proximity labeling of protein networks associated with ligand-activated EGFR

“…To test whether TFG is involved in endosomal sorting of ligand-free EGFR, we used a model of HeLa/FAP-EGFR cells in which EGFR internalization is induced by tumor necrosis factor alpha (TNF-a) (Perez Verdaguer et al, 2021). TNF-a transiently activates internalization of ligand-free EGFR mediated by stress-activated p38/MAPK, which is followed by recycling but not degradation (Tanaka et al, 2018).…”