Figure 8. Signaling mechanism of HGF-induced attenuation of GEF-H1 activity and barrier disruptive Rho signaling via Rac1-dependent stimulation of peripheral microtubule network.

HGF engages c-Met receptor and triggers Rac1 activity, leading to activation of PAK1. PAK1-mediated phosphorylation of stathmin inhibits its MT destabilizing activity and promotes the growth of the peripheral MT network leading to immobilization and inactivation of Rho-specific guanine nucleotide exchange factor GEF-H1. As a result, MT-dependent GEF-H1 inactivation attenuates agonist induced Rho signaling leading to recovery of peripheral actin cytoskeleton and restoration of endothelial barrier.