Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and recycling

Abstract

SummaryCells inversely adjust the plasma membrane levels of integrins and cadherins during cell migration and cell-cell adhesion but the regulatory mechanisms that coordinate these trafficking events remain unknown. Here, we demonstrate that the small GTPase Rab35 maintains cadherins at the cell surface to promote cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase Arf6 to downregulate an Arf6-dependent recycling pathway for b1-integrin and EGF receptors, resulting in inhibition of cell migration and attenuation of signaling downstream of these receptors. Importantly, the phenotypes of decreased cell adhesion and increased cell migration observed following Rab35 knock down are consistent with the epithelial-mesenchymal transition, a feature of invasive cancer cells, and we show that Rab35 expression is suppressed in a subset of cancers characterized by Arf6 hyperactivity. Our data thus identify a key molecular mechanism that efficiently coordinates the inverse intracellular sorting and cell surface levels of cadherin and integrin receptors for cell migration and differentiation.

Structure-Function Analyses of the Small GTPase Rab35 and Its Effector Protein Centaurin-β2/ACAP2 during Neurite Outgrowth of PC12 Cells

“…We also showed by knockdown-rescue experiments that centaurin-␤2 functions as a Rab35 effector during NGF-induced neurite outgrowth of PC12 cells. The Rab35 SR (T76S/T81A) mutant that we developed should be a powerful, easy-to-use tool for probing the involvement of centaurin-␤2 in Rab35-dependent cellular events, including cytokinesis (15), cell migration (17,18), and phagocytosis (19,20), at the cellular level.…”

“…Rab35 is one such Rab protein and has been shown to bind various candidate effector molecules, including MICAL-1 (7), MICAL-L1 (7,9,10), MICAL-cl (7), OCRL (7,11), RUSC2 (12), Fascin1 (13), and centaurin-␤2 (8,14), and to be involved in various cellular events, including cytokinesis (11,15,16), cell migration (17,18), phagocytosis (19,20), immunological synapse formation (21), myelination (22), and neurite outgrowth (10,14,23,24), most likely through regulation of endocytic recycling (25). The pleiotropic roles of Rab35 in membrane trafficking may be attributable to the presence of multiple Rab35 effectors, but the involvement of individual Rab35 effectors in the above cellular events has remained largely unknown.…”

A novel interaction between Rab7b and actomyosin reveals a dual role in intracellular transport and cell migration

“…Other Rab proteins that interact with members of the myosin family also interfere with the process of cell migration (Seabra and Coudrier, 2004;Allaire et al, 2013). However, their effects on cell migration have so far been investigated only in connection to the well-established role of Rabs in intracellular trafficking (Kawauchi et al, 2010;Mai et al, 2011;Linford et al, 2012;Allaire et al, 2013;Wiesner et al, 2013).…”

On the move: endocytic trafficking in cell migration

“…The surface levels of cadherins and integrins for instance tend to be inversely modulated during cell migration. This is achieved via the small GTPase Rab35 which promotes the surface localization of cadherins while at the same time inhibiting Arf6 and thereby down-regulating the Arf6-dependent recycling pathway for b1-integrins and EGFRs [113].…”