Compressive mechanical stress activates ERK5 to regulate cortical tension and promote invasive cellular traits

Growth-induced compressive forces regulate diverse biological processes ranging from development to tumor progression, but the underlying molecular mechanisms remain poorly understood. Here, we found that compressive mechanical cues activate the MAP kinase extracellular signal-regulated kinase 5 (ERK5) at the cell periphery, inducing invasive traits in epithelial cells. Using a phospho-proteomic approach combined with an RNAi-based validation screen, we identified several previously unrecognized ERK5 effectors important for cell-cell adhesion and actin organization, among them the myosin light chain (MLC) phosphatase subunit Myosin Phosphatase-Targeting Subunit 1 (MYPT1). Our results demonstrate that ERK5 regulates MYPT1, which in turn inhibits myosin at the cell periphery. ERK5 signaling counteracts Rho-associated protein kinase (ROCK), thereby reducing peripheral actomyosin tension. This relaxation destabilizes cell-cell contacts and promotes cell migration in response to mechanical compression. Together, these findings identify an ERK5-mediated response mechanism activated by compressive force that triggers cell invasion, highlighting ERK5 therapeutic potential.