Wnt5a controls cell polarity and directional movement through trafficking and polarized redistribution of cell adhesion receptors

Mechanisms by which beta‐catenin‐independent Wnt pathways integrate the organization of receptors, organelles, and cytoskeletal proteins in order to confer cell polarity and directional cell movement are incompletely understood. Here, we show that acute responses to Wnt5a involve recruitment of actin, myosin IIB, Frizzled 3 and melanoma cell adhesion molecule into a novel intracellular structure, which we named the “MCAM locus”. In the presence of a chemokine gradient, the MCAM locus accumulates asymmetrically at the cell periphery, where it triggers membrane contractility and nuclear movement in the direction of membrane retraction. The process requires endosome trafficking associated with recruitment of multivesicular bodies, and is regulated by Wnt5a signaling via Rab4 and RhoB. These findings reveal a novel cell‐autonomous mechanism by which Wnt5a controls cell orientation, polarity, and directional movement in response to positional cues from ligand gradients.