Piezo1 activates noncanonical EGFR endocytosis and signaling

Abstract

EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.

The Plasma Membrane and Mechanoregulation in Cells

“…Stretch-induced Piezo1 activation plays a key role in the cell cycle and thus dysregulation of mechanotransduction that results in an imprudent trigger of the Piezo1 channel can initiate cancer due to excessive cell proliferation. 43 Clathrin and dynamin 2 (DNM2) are the key proteins of intracellular membrane trafficking that are coexpressed at specialized adhesion and force-transmitting sites of muscle fibers called costameres ( Figure 2 b). These assemblies link the PM to the extracellular matrix and the contractile units of muscle, therefore mutations in these components cause several distinct myopathies.…”