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bioRxiv · 10.1101/2024.10.01.616161

Long range mutual activation establishes Rho and Rac polarity during cell migration

De Belly, H.·Gallen, A. F.·Strickland, E.·Estrada, D. C.·Zager, P. J.·Burkhardt, J. K.·Turlier, H.·Weiner, O.
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Abstract

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. We show that 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, indicating 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.

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De Belly, H., Gallen, A. F., Strickland, E., Estrada, D. C., Zager, P. J., Burkhardt, J. K., Turlier, H., Weiner, O.. 2024-10-02. Long range mutual activation establishes Rho and Rac polarity during cell migration. https://doi.org/10.1101/2024.10.01.616161

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