Rab35 and Arf6: a balancing act

The levels of integrins and cadherins at the plasma membrane need to be carefully balanced by the cell during cell migration and adhesion, but how the trafficking events that coordinate these levels are regulated is unknown. On page 722, Peter McPherson and colleagues examine the interdependence of two small GTPases, Rab35 and Arf6, on the recycling of adhesion molecules, cell–cell interactions and cell migration. They show that Rab35 knockdown enhances the intracellular accumulation of cadherins, correlating with reduced cell–cell adhesion. The loss of Rab35 also increases recycling of β1 integrin and epidermal growth factor receptor, and signalling to focal adhesion kinase, correlating with enhanced cell migration. Rab35 is known to recruit the Arf6 GTPase-activating protein (GAP) ACAP2 to inactivate Arf6, whereas Arf6 recruits Rab35 GAPs to inactivate Rab35; the authors show, however, that Rab35 knockdown significantly enhances endogenous Arf6 activity, providing direct evidence that Rab35 is a negative regulator of Arf6. In addition, simultaneous knockdown of Rab35 and Arf6 reverses the enhanced cell migration induced by Rab35 knockdown, indicating that Rab35 suppresses Arf6 to limit cell migration. Interestingly, the authors find that Rab35 mRNA levels are suppressed in certain tumour cells, which could explain the hyperactivity of Arf6 in many tumours. These data therefore identify a key molecular mechanism for coordinating the antagonistic functions of cell migration and differentiation.