Rab11 regulates cell–cell communication during collective cell movements

Abstract

Collective cell movements contribute to development and metastasis. The small GTPase Rac is a key regulator of actin dynamics and cell migration but the mechanisms that restrict Rac activation and localization in a group of collectively migrating cells are unknown. Here, we demonstrate that the small GTPases Rab5 and Rab11 regulate Rac activity and polarization during collective cell migration. We use photoactivatable forms of Rac to demonstrate that Rab11 acts on the entire group to ensure that Rac activity is properly restricted to the leading cell through regulation of cell–cell communication. In addition, we show that Rab11 binds to the actin cytoskeleton regulator Moesin and regulates its activatio in vivo during migration. Accordingly, reducing the level of Moesin activity also affects cell–cell communication, whereas expressing active Moesin rescues loss of Rab11 function. Our model suggests that Rab11 controls the sensing of the relative levels of Rac activity in a group of cells, leading to the organization of individual cells in a coherent multicellular motile structure.

Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a

“…Rac1 and Rab11 have been shown to interact genetically in Drosophila (Assaker et al, 2010). Recently, Emery and Ramel have suggested that Rab11 is involved in the spatiotemporal regulation of Rac activity during collective cell movement during Drosophila oogenesis Ramel et al, 2013) and Rab11FIP3, which binds Arf6, can regulate polarized Rac1 activation in HeLa cells (Jing et al, 2009). These reports together with our data indicate that reggie and Rab11 might regulate Rac1 recruitment and its spatially confined activation.…”

On the move: endocytic trafficking in cell migration

“…The expression of dominant negative Rab5 in border cells abolishes Rac activation which reinforces the crucial role of endocytic trafficking for the regulation of Rac activity [43]. Interestingly, the expression of a dominant negative Rab11 variant caused a divergent phenotype: Instead of being confined to the leading cell the signal peak for activated Rac alternated between different cells or was present in multiple cells at once [43]. Thus, Rab11 seems to regulate the polarization and persistence of Rac activity in the leading cell of a collectively migrating cell cluster and to control the spatial pattern of Rac activity across the cluster [43].…”

“…Here Rac signaling does not only need to be restricted to the leading edge of an individual cell, but should be specifically enriched in the leading cell. The expression of dominant negative Rab5 in border cells abolishes Rac activation which reinforces the crucial role of endocytic trafficking for the regulation of Rac activity [43]. Interestingly, the expression of a dominant negative Rab11 variant caused a divergent phenotype: Instead of being confined to the leading cell the signal peak for activated Rac alternated between different cells or was present in multiple cells at once [43].…”

“…Interestingly, the expression of a dominant negative Rab11 variant caused a divergent phenotype: Instead of being confined to the leading cell the signal peak for activated Rac alternated between different cells or was present in multiple cells at once [43]. Thus, Rab11 seems to regulate the polarization and persistence of Rac activity in the leading cell of a collectively migrating cell cluster and to control the spatial pattern of Rac activity across the cluster [43]. How Rab11 as an endosomal trafficking protein achieves this intercellular coordination of Rac activity remains a mystery for the moment.…”

Rho GTPase isoforms in cell motility: Don't fret, we have FRET

“…For example, the pathways regulating activation of Rac1 in the control of Drosophila border cell migration were elucidated in a number of studies using the Rac1 biosensor. 75,76 Furthermore, the importance of the Rac1 GEFs, PLCe,Tiam1 and Trio in fibroblast chemotaxis, T-cell migration and invasion and tumor cell invasion, respectively were determined in studies that employed Rac1 FRET biosensors 74,77,78 In addition to probes that monitor the activation status of Rac1 in cells, optical tools have also been developed that allow the direct, localized manipulation of Rac1 activity. A genetically encoded photoactivatable Rac1 was engineered in which Rac1 is fused to the LOV domain, which sterically hinders the ability of Rac1 to interact with downstream effectors.…”