Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization

Abstract

Rac1 GTPase is hyper-activated in tumours and contributes to malignancy.Rac1 disruption of junctions requires its effector PAK1, but the precise mechanisms are unknown. Here we identify that E-cadherinis internalized via micropinocytosis in a PAK1–dependent manner, without catenin dissociation and degradation. In addition to internalization, PAK1 regulates E-cadherin transport by fine-tuning Rab small GTPase function. PAK1 phosphorylates RabGDI(a core Rab regulator), but not RabGDI. Phosphorylated RabGDIpreferentiallyassociateswith Rab5 and Rab11, which is predicted to promote Rab retrieval from membranes. Consistent with this hypothesis, Rab11is activated by hyper-activeRac1andinhibition of Rab11 function partially rescues E-cadherin destabilization. Thus, Rac1 activation reduces surface cadherin levels as a net result of higher bulk flow of membrane uptake that counteractsRab11-dependentE-cadherin delivery to junctions (recycling and/or exocytosis). This unique small GTPase crosstalk has impact onRac1 and PAK1regulation of membrane remodelling during epithelial de-differentiation, adhesion and motility.