title: Interplay between Rab35 and Arf6 controls cargo recycling to coordinate cell adhesion and migration.
abstract: Cells 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 β1-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.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Allaire
authors.forename: Mohamed
authors.initials: M
authors.lastname: Seyed Sadr
authors.forename: Mathilde
authors.initials: M
authors.lastname: Chaineau
authors.forename: Emad
authors.initials: E
authors.lastname: Seyed Sadr
authors.forename: Sarah
authors.initials: S
authors.lastname: Konefal
authors.forename: Maryam
authors.initials: M
authors.lastname: Fotouhi
authors.forename: Deborah
authors.initials: D
authors.lastname: Maret
authors.forename: Brigitte
authors.initials: B
authors.lastname: Ritter
authors.forename: Rolando F
authors.initials: RF
authors.lastname: Del Maestro
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002522:Chlorocebus aethiops; D051181:Desmosomal Cadherins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D051181:Desmosomal Cadherins; D019012:Integrin beta1; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; C511183:RAB35 protein, human; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; D020691:rab GTP-Binding Proteins