Long range mutual activation establishes Rho and Rac polarity during cell migration - Nat Cell Biol

H. De Belly*, A. Fernandez Gallen, E. Strickland, D.C. Estrada, D.S. Godinez, E.M. Neiva, P.J. Zager, T.L. Nagy, J.K. Burkhardt, H. Turlier*, O.D. Weiner*, Nature Cell Biology (accepted)

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In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back.  How these GTPases are appropriately positioned at the opposite poles of migrating cells is unknown.  Here we leverage optogenetics, manipulation of cell mechanics, and mathematical modeling to reveal a surprising mechanochemical long-range mutual activation of the front and back polarity programs that complements their well-known local mutual inhibition.  Rac-based protrusion stimulates Rho activation at the opposite side of the cell via membrane tension-based activation of mTORC2.  Conversely, Rho-based contraction induces cortical-flow-based regulation of phosphoinositide signaling to trigger Rac activation at the opposite side of the cell.  We develop a minimal unifying mechanochemical model of the cell to explain how this long-range facilitation complements local inhibition to enable robust Rho and Rac partitioning.  This long-range mutual activation of Rac and Rho is conserved in epithelial cells and is also essential for efficient polarity and migration of primary human T cells, showing the generality of this circuit.  Our findings demonstrate that the actin cortex and plasma membrane function as an integrated mechanochemical system for long-range partitioning of Rac and Rho during cell migration and likely other cellular contexts.