ERK1/2 mitogen-activated protein kinase dimerization is essential for the regulation of cell motility

Abstract

ERK1/2 mitogen-activated protein kinases (ERK) are key regulators of basic cellular processes, including proliferation, survival, and migration. Upon phosphorylation, ERK becomes activated and a portion of it dimerizes. The importance of ERK activation in specific cellular events is generally well documented, but the role played by dimerization is largely unknown. Here, we demonstrate that impeding ERK dimerization precludes cellular movement by interfering with the molecular machinery that executes the rearrangements of the actin cytoskeleton. We also show that a constitutively dimeric ERK mutant can drive cell motility per se, demonstrating that ERK dimerization is both necessary and sufficient for inducing cellular migration. Importantly, we unveil that the scaffold protein kinase suppressor of Ras 1 (KSR1) is a critical element for endowing external agonists, acting through tyrosine kinase receptors, with the capacity to induce ERK dimerization and, subsequently, to unleash cellular motion. In agreement, clinical data disclose that high KSR1 expression levels correlate with greater metastatic potential and adverse evolution of mammary tumors. Overall, our results portray both ERK dimerization and KSR1 as essential factors for the regulation of cell motility and mammary tumor dissemination.

We are indebted to Dr D. Engelberg for providing reagents. PC lab is supported by grant PID2021-126288OB-I00 and PDC2022-133569-I00 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE); CIBERONC (CB16/12/00436) from the Instituto de Salud Carlos III (ISCIII); and a grant from ASPLA S.A "Encintalo en Rosa" Initiative. BC is funded by grants from Ministerio de Innovación, Ciencia y Universidades, MICIU PID2020/112760RB-100 and La Fundació d'Estudis i Recerca Oncològica (FERO, BFERO2021.03). JA is supported by CIBERONC; Breast Cancer Research Foundation (BCRF-23-008) and Instituto de Salud Carlos III (ISCIII) (PI22/00001). AK is supported by the Wellcome Trust (Multiuser Equipment Grant, 208402/Z/17/Z). DF-V is a CIBERONC predoctoral fellow (JCSTF2105526).