Abstract
Migrating cells need to coordinate distinct leading and trailing edge dynamics but the underlying mechanisms are unclear. Here, we combine experiments and mathematical modeling to elaborate the minimal autonomous biochemical machinery necessary and sufficient for this dynamic coordination and cell movement. RhoA activates Rac1 via DIA and inhibits Rac1 via ROCK, while Rac1 inhibits RhoA through PAK. Our data suggest that in motile, polarized cells, RhoA-ROCK interactions prevail at the rear, whereas RhoA-DIA interactions dominate at the front where Rac1/Rho oscillations drive protrusions and retractions. At the rear, high RhoA and low Rac1 activities are maintained until a wave of oscillatory GTPase activities from the cell front reaches the rear, inducing transient GTPase oscillations and RhoA activity spikes. After the rear retracts, the initial GTPase pattern resumes. Our findings show how periodic, propagating GTPase waves coordinate distinct GTPase patterns at the leading and trailing edge dynamics in moving cells.
Highlights
Cell migration relies on the coordination of actin dynamics at the leading and the trailing edges (Ridley et al, 2003)
Using proximity ligation assays (PLA), we show that the concentration of complexes formed by Ras homolog family member A (RhoA) and its downstream effectors Diaphanous related formin-1 (DIA) and Rho-associated kinase (ROCK) depends on the spatial location along the longitudinal axis of polarized cells
The decrease of relative related C3 botulinum toxin substrate 1 (Rac1) and RhoA activities induced by DIA knockdown shows that DIA activates Rac1 and supports the existence of a positive feedback loop between DIA and RhoA described earlier (Kitzing et al, 2007)
Summary
Cell migration relies on the coordination of actin dynamics at the leading and the trailing edges (Ridley et al, 2003). Core biochemical mechanisms of this dynamic cycle are governed by the Rho family of small GTPases (Jaffe and Hall, 2005). Two members of this family, Ras homolog family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac1), control protrusions and retractions at the leading edge as well as the contractility at the rear (Felmet et al, 2005; Heasman and Ridley, 2008; Machacek et al, 2009). Switches between on and off states are tightly regulated by (i) guanine nucleotide exchange factors (GEFs) that facilitate GDP/GTP
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