An ARF6/Rab35 GTPase cascade for endocytic recycling and successful cytokinesis

Laurent Chesneau, Daphné Dambournet, Mickaël MacHicoane, Ilektra Kouranti, Mitsunori Fukuda, Bruno Goud, Arnaud Echard

    Research output: Contribution to journalArticlepeer-review

    112 Citations (Scopus)


    Cytokinesis bridge instability leads to binucleated cells that can promote tumorigenesis in vivo [1]. Membrane trafficking is crucial for animal cell cytokinesis [2-8], and several endocytic pathways regulated by distinct GTPases (Rab11, Rab21, Rab35, ARF6, RalA/B) [9-16] contribute to the postfurrowing steps of cytokinesis. However, little is known about how these pathways are coordinated for successful cytokinesis. The Rab35 GTPase controls a fast endocytic recycling pathway and must be activated for SEPTIN cytoskeleton localization at the intercellular bridge, and thus for completion of cytokinesis [12]. Here, we report that the ARF6 GTPase [17, 18] negatively regulates Rab35 activation and hence the Rab35 pathway. Human cells expressing a constitutively activated, GTP-bound ARF6 mutant display identical endocytic recycling and cytokinesis defects as those observed upon overexpression of the inactivated, GDP-bound Rab35 mutant. As a molecular mechanism, we identified the Rab35 GAP EPI64B as an effector of ARF6 in negatively regulating Rab35 activation. Unexpectedly, this regulation takes place at clathrin-coated pits, and activated ARF6 reduces Rab35 loading into the endocytic pathway. Thus, an effector of an ARF protein is a GAP for a downstream Rab protein, and we propose that this hierarchical ARF/Rab GTPase cascade controls the proper activation of a common endocytic pathway essential for cytokinesis.

    Original languageEnglish
    Pages (from-to)147-153
    Number of pages7
    JournalCurrent Biology
    Issue number2
    Publication statusPublished - 2012 Jan 24

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)


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