MAP4K4 regulates biomechanical forces at adherens junctions and focal adhesions to promote collective cell migration

Abstract

Collective cell migration is important for normal development and tissue homeostasis, but can also promote cancer metastasis. To migrate collectively, cells need to coordinate their protrusion formation, rear retraction, adhesion sites dynamics, as well as forces generation and transmission. Nevertheless, the regulatory mechanisms coordinating these processes remain elusive. Using the A431 carcinoma cell line, we identify the kinase MAP4K4 as a central regulator of collective migration. We show that MAP4K4 inactivation blocks the migration of clusters while its overexpression decreases cluster cohesion. MAP4K4 regulates protrusion and retraction dynamics, remodels the actomyosin cytoskeleton, and controls the stability of both cell-cell and cell substrate adhesion. MAP4K4 promotes focal adhesion disassembly through the phosphorylation of Moesin, an actin and plasma membrane cross-linker, but disassembles adherens junctions through a Moesin-independent mechanism. By analyzing traction and intercellular forces, we found that the stabilization of adhesion sites in MAP4K4 loss of function leads to a tensional disequilibrium throughout the cell cluster, increasing the traction forces exerted onto the substrate and the tension loading at the cell-cell adhesions. Together, our results indicates that MAP4K4 activity is a key regulator of biomechanical forces at adhesion sites, promoting collective migration.