Rab7a regulates cell migration through Rac1 and vimentin

Abstract

Rab7a, a small GTPase of the Rab family, is localized to late endosomes and controls late endocytic trafficking. The discovery of several Rab7a interacting proteins revealed that Rab7a function is closely connected to cytoskeletal elements. Indeed, Rab7a recruits on vesicles RILP and FYCO that are responsible for the movement of Rab7a-positive vesicles and/or organelles on microtubule tracks, but also directly interacts with Rac1, a fundamental regulator of actin cytoskeleton, and with peripherin and vimentin, two intermediate filament proteins. Considering all these interactions and, in particular, the fact that Rac1 and vimentin are key factors for cellular motility, we investigated a possible role of Rab7a in cell migration. We show here that Rab7a is needed for cell migration as Rab7a depletion causes slower migration of NCI H1299 cells affecting cell velocity and directness.Rab7a depletion negatively affects adhesion and spreading onto fibronectin substrates, altering β1-integrin activation, localization and intracellular trafficking, and myosin X localization. In fact, Rab7a-depleted cells show 40% less filopodia and active integrin accumulates at the leading edge of migrating cells. Furthermore, Rab7a depletion decreases the amount of active Rac1 but not its abundance and reduces the number of cells with vimentin filaments facing the wound, indicating that Rab7a has a role in the orientation of vimentin filaments during migration. In conclusion, our results demonstrate a key role of Rab7a in the regulation of different aspects of cell migration.

Characterization of the role of RILP in cell migration

“…11,33 Furthermore, we recently demonstrated that Rab7a controls cell migration by influencing adhesion and spreading on fibronectin. 14 Here, we demonstrated that also RILP plays a role in cell adhesion and spreading to fibronectin. Indeed, RILP overexpression decreased the adhesion and spreading on fibronectin compared to control cells (Figures 4 and 5).…”

“…This is interesting considering that alterations of migration are found in cancer cells and that also Rab7a regulates migration. 14 In particular, Rab7a seems to favor or suppress cancer progression depending on the cell type or district of tumor. 17,29,30 Indeed, Rab7a oncosuppressing role has been demonstrated in prostate cancer cells where its depletion affected lysosome localization, increasing tumor cell invasion.…”

“…Indeed, as RILP-C33 does not interact with the dynactin-dynein complex, and does not affect tubulin filaments rearrangements during migration (Figure 3), another RILP interactor could be responsible for the effect on cell adhesion and spreading mediated by RILP. RILP-C33 is able to interact with Rab7a, which has been recently shown to have a role in cell spreading, 14 therefore this small GTPase could be involved in the regulation of cell adhesion and spreading mediated by RILP.…”

Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

“…In addition, HGF stimulation also induced c-Met-dependent Rac1 activation in perinuclear, Rab7-positive endosomes by engaging the specific effectors PI3K and the GEF Vav2 to activate cell migration and invasion [125]. Additionally, Rab7 was shown to directly interact with Rac1 on endosomes, thereby enabling Rac1 activation and promoting Rac1 delivery to the PM to stimulate cell migration [129]. On the other side, RhoB was shown to act as a negative regulator of Rac1 activity.…”

Unconventional Transport Routes of Soluble and Membrane Proteins and Their Role in Developmental Biology

“…Progida presented the results of the motility screens and control experiments for reduced cell proliferation. Their recent results demonstrating that one of the candidates, RAB7a, does regulate cell migration has just been published [77]. Like RAB7b, RAB7a also regulates the actin cytoskeleton, but through interactions with RAC1 and vimentin.…”