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  • Title: Spatiotemporal dynamics of GEF-H1 activation controlled by microtubule- and Src-mediated pathways.
    Author: Azoitei ML, Noh J, Marston DJ, Roudot P, Marshall CB, Daugird TA, Lisanza SL, Sandí MJ, Ikura M, Sondek J, Rottapel R, Hahn KM, Danuser G.
    Journal: J Cell Biol; 2019 Sep 02; 218(9):3077-3097. PubMed ID: 31420453.
    Abstract:
    Rho family GTPases are activated with precise spatiotemporal control by guanine nucleotide exchange factors (GEFs). Guanine exchange factor H1 (GEF-H1), a RhoA activator, is thought to act as an integrator of microtubule (MT) and actin dynamics in diverse cell functions. Here we identify a GEF-H1 autoinhibitory sequence and exploit it to produce an activation biosensor to quantitatively probe the relationship between GEF-H1 conformational change, RhoA activity, and edge motion in migrating cells with micrometer- and second-scale resolution. Simultaneous imaging of MT dynamics and GEF-H1 activity revealed that autoinhibited GEF-H1 is localized to MTs, while MT depolymerization subadjacent to the cell cortex promotes GEF-H1 activation in an ~5-µm-wide peripheral band. GEF-H1 is further regulated by Src phosphorylation, activating GEF-H1 in a narrower band ~0-2 µm from the cell edge, in coordination with cell protrusions. This indicates a synergistic intersection between MT dynamics and Src signaling in RhoA activation through GEF-H1.
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