Define how EGFR is regulated by mechanical signaling during stem cell commitment.

EGFR, a receptor tyrosine kinase, initiates signaling through ligand-induced conformational changes. We aim to better understand this initiation event and its regulation as various specific EGFR ligands can change downstream signaling dynamics and drive cell fate decisions. The tumor suppressor Merlin has been identified as a crucial inhibitor of EGFR internalization and signaling. Merlin is also essential at the cortical cytoskeleton, where it regulates EGFR internalization upon cell-cell contact. Importantly, Merlin has been established as mechanosensor, which responds rapidly to changes in epithelial monolayer tension. Merlin, positioned in the cortical actomyosin network of colonic stem cells, transmits mechanical signals from cell-cell contacts to regulate EGFR dynamics and mechanoresponsive transcription programs. These data suggest that merlin could be responding to mechanical cures to trap EGFR when signaling is not needed, but keep it in a primed state for activation, as has been shown recently with the junctional protein E-cadherin. We hypothesize that apical contractility in stem cells releases Merlin, activating EGFR and enhancing stem cell renewal, while wounded/apoptotic cells emit pro-migratory signals that increase long-range tension towards the stem cell niche to release merlin, transiently activate EGFR, and drive stem cell commitment.