E-cadherin mechanotransduction activates EGFR/ERK signaling by inducing ligand shedding

ABSTRACT: The behavior of cells is governed by signals originating from their local environment, including mechanical forces that cells experience. Forces are transduced by mechanosensitive proteins, which can impinge on signaling cascades that are also activated by growth factor receptors upon ligand binding. However, the interplay between these mechanical and biochemical signals in the regulation of intracellular signaling networks remains incompletely understood. To elucidate this mechanochemical crosstalk, we conducted phosphoproteomic and transcriptomic analyses on epithelial cells subjected to mechanical strain. This approach revealed ERK signaling as a predominant hub activated in response to intercellular forces, initiated at the level of the upstream EGF receptor. Strain-induced EGFR/ERK signaling relies on mechanosensitive E-cadherin adhesions, as it is disrupted upon genetic modulation of force transduction by the E-cadherin complex. Proximity labeling identified a connection between E-cadherin and ADAM17, an enzyme that mediates the shedding of soluble EGFR ligands. We developed a novel ADAM probe that showed that mechanical strain induces ADAM17 activity, which is essential for relaying forces to EGFR/ERK signaling. Collectively, our data demonstrate how forces transduced by E-cadherin adhesion modulate the presence of EGFR ligands to regulate downstream ERK activity. Our findings illustrate how intercellular forces and biochemical ligands can operate within a single, linear signaling cascade.

INSTRUMENT(S):

ORGANISM(S): Canis Familiaris (dog) (canis Lupus Familiaris)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Harmjan Vos  

LAB HEAD: Martijn Gloerich

PROVIDER: PXD052926 | Pride | 2025-11-18

REPOSITORIES: Pride