Activated Rac1 binds to and stimulates the kinase activity of PAK1-3 (p21 activated kinases 1-3). PAK dimers are arranged in head-to-tail fashion, in which the kinase domain of one molecule is inhibited by the regulatory domain of the other molecule and vice versa. Binding of activated Rac1 breaks the PAK dimer and removes the trans-inhibition (Knaus et al. 1998, Parrini et al. 2002). PAK activated by Rac1 in turn phosphorylates VE-cadherin thereby promoting the beta-arestin-dependent endocytosis of VE-cadherin. This consequently disassemblies intracellular junctions leading to vascular permeability (Gavard & Gutkind 2006).