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Rab11 regulates cell–cell communication during collective cell movements

Nature Cell Biology volume 15, pages 317–324 (2013)Cite this article

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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 activation 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.

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Figure 1: Rab proteins regulate actin dynamics and Rac activity and polarization.
Figure 2: Local activation of Rac does not rescue the Rab11 loss-of-function phenotype.
Figure 3: Local inactivation of Rac reveals a role in cell–cell communication for Rab11.
Figure 4: Rab11 interacts with and controls Moesin activity.
Figure 5: Moesin regulates protrusion distribution, polarization of Rac activity and cell–cell communication.

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Acknowledgements

We thank the Bloomington Stock Collection and the Vienna Drosophila RNAi Center for fly stocks. We thank G. Assaker, C. Iampietro and C. Charbonneau for technical assistance and helpful discussions. We also thank S. Carreno for providing important insights on Moesin experiments. This work was supported by grants from the Canadian Institute for Health Research (CIHR) to G.E. (MOP-114899). G.E. holds a Canada Research Chair (Tier II) in Vesicular Trafficking and Cell Signalling. D.R. and C.L. are supported by Fonds de Recherche Québec Santé (FRQS). X.W. is supported by the Atip-Avenir programme and the Centre National de la Recherche Scientifique (CNRS). D.M. is supported by grants R01GM46425 and R01GM73164. IRIC is supported in part by the Canadian Center of Excellence in Commercialization and Research (CECR), the Canada Foundation for Innovation (CFI) and by the Fonds de Recherche du Québec en Santé (FRQS). This paper is dedicated to the memory of A. Ruffé.

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Author notes

  1. Xiaobo Wang

    Present address: Present addresses: Université de Toulouse, UPS, F-31062 Toulouse, France; CNRS, LBCMCP, F-31062 Toulouse, France,

Authors and Affiliations

  1. Institute for Research in Immunology and Cancer (IRIC) and Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Quebec, H3C 3J7, Canada

    Damien Ramel, Carl Laflamme & Gregory Emery

  2. Department of Biological Chemistry, Center for Cell Dynamics, Johns Hopkins School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, USA

    Xiaobo Wang & Denise J. Montell

Authors
  1. Damien Ramel
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Contributions

G.E. and D.R. conceived the project and G.E. directed it. D.R. designed and performed FRET experiments, staining of border cells and egg chambers, quantified migration, and developed the method for determination of the orientation of the protrusions. D.R. and X.W. performed photoactivation experiments. C.L. developed mass spectrometry analysis and immunoprecipitations. D.R., D.J.M. and G.E. wrote the manuscript.

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Correspondence to Gregory Emery.

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Supplementary information

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PA-RacQ61L photoactivation in a control background.

Border cells expressing UAS-PA-RacQ61L at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 6481 kb)

PA-RacQ61L photoactivation in a Rab11SN background.

Border cells expressing UAS-PA-RacQ61L and Rab11SN at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 7812 kb)

PA-RacQ61L photoactivation in a Rab5SN background.

Border cells expressing UAS-PA-RacQ61L and Rab5SN at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 8702 kb)

Light-insensitive RacQ61L photoactivation in a Rab11SN background.

Border cells expressing UAS-PA-RacQ61L C450M and Rab11SN at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 9817 kb)

Light-insensitive RacQ61L photoactivation in a Rab5SN background.

Border cells expressing UAS-PA-RacQ61L C450M and Rab5SN at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 8046 kb)

PA-RacT17N photoactivation in a control background.

Border cells expressing UAS-PA-RacT17N at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation as described in Materials and Methods. The green circle represents the area of photoactivation. (AVI 2686 kb)

PA-RacT17N Photoactivation in a Rab11SN background.

Border cells expressing UAS-PA-RacT17N and Rab11SN at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 3385 kb)

PA-RacT17N photoactivation in a Rab5SN background.

Border cells expressing UAS-PA-RacT17N and Rab5SN at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 5977 kb)

PA-RacT17N photoactivation in an RNAi Moesin background.

Border cells expressing UAS-PA-RacT17N and RNAi Moesin at the onset of migration were recorded by time-lapse microscopy and subjected to photoactivation (as described in Methods). The green circle represents the area of photoactivation. (AVI 2150 kb)

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Ramel, D., Wang, X., Laflamme, C. et al. Rab11 regulates cell–cell communication during collective cell movements. Nat Cell Biol 15, 317–324 (2013). https://doi.org/10.1038/ncb2681

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