1. Academic Validation
  2. MAP4K4 regulates forces at cell-cell and cell-matrix adhesions to promote collective cell migration

MAP4K4 regulates forces at cell-cell and cell-matrix adhesions to promote collective cell migration

  • Life Sci Alliance. 2023 Jun 27;6(9):e202302196. doi: 10.26508/lsa.202302196.
Lara Elis Alberici Delsin 1 Cédric Plutoni 1 Anna Clouvel 2 Sarah Keil 1 Léa Marpeaux 1 Lina Elouassouli 1 Adele Khavari 2 Allen J Ehrlicher 2 Gregory Emery 3 4
Affiliations

Affiliations

  • 1 Vesicular Trafficking and Cell Signalling Research Unit, Institute for Research in Immunology and Cancer https://ror.org/0161xgx34 (IRIC), Université de Montréal, Montréal, Canada.
  • 2 Department of Bioengineering, McGill University, Montreal, Canada.
  • 3 Vesicular Trafficking and Cell Signalling Research Unit, Institute for Research in Immunology and Cancer https://ror.org/0161xgx34 (IRIC), Université de Montréal, Montréal, Canada gregory.emery@umontreal.ca.
  • 4 Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Canada.
Abstract

Collective cell migration is not only important for development and tissue homeostasis but can also promote Cancer metastasis. To migrate collectively, cells need to coordinate cellular extensions and retractions, adhesion sites dynamics, and forces generation and transmission. Nevertheless, the regulatory mechanisms coordinating these processes remain elusive. Using A431 carcinoma cells, we identify the kinase MAP4K4 as a central regulator of collective migration. We show that MAP4K4 inactivation blocks the migration of clusters, whereas 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 the actin and plasma membrane crosslinker moesin but disassembles adherens junctions through a moesin-independent mechanism. By analyzing traction and intercellular forces, we found that MAP4K4 loss of function leads to a tensional disequilibrium throughout the cell cluster, increasing the traction forces and the tension loading at the cell-cell adhesions. Together, our results indicate that MAP4K4 activity is a key regulator of biomechanical forces at adhesion sites, promoting collective migration.

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