Rho family small GTPases regulate processes such as cell migration, adhesion, proliferation and differentiation. They are activated by guanine nucleotide exchange factors (GEFs), which catalyze the exchange of GDP for GTP. GEF-H1 is a Rho GEF that localizes to microtubules and regulates Rho activity in response to microtubule destabilization (1). Loss of interaction between GEF-H1 and microtubules leads to activation of Rho (2). PAK1 phosphorylates GEF-H1 at Ser885, a site located in the 14-3-3 binding motif. Phosphorylation at this site is required for 14-3-3 binding and correlated to recruitment of 14-3-3 and GEF-H1 to microtubules (3). GEF-H1 has also been shown to localize to tight junctions and modulate polarized cell permeability (4,5). GEF-H1 is inactivated by binding to cingulin at epithelial tight junctions, inactivating RhoA and leading to G1/S arrest (5).