A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

Martina Zobel, Andrea Disanza, Francesca Senic-Matuglia, Michel Franco, Ivan Nicola Colaluca, Stefano Confalonieri, Sara Bisi, Elisa Barbieri, Giusi Caldieri, Sara Sigismund, Salvatore Pece, Philippe Chavrier, Pier Paolo Di Fiore, Giorgio Scita

Research output: Contribution to journalArticle


The endocytic protein NUMB has been implicated in the control of various polarized cellular processes, including the acquisition of mesenchymal migratory traits through molecular mechanisms that have only been partially defined. Here, we report that NUMB is a negative regulator of a specialized set of understudied, apically restricted, actin-based protrusions, the circular dorsal ruffles (CDRs), induced by either PDGF or HGF stimulation. Through its PTB domain, NUMB binds directly to an N-terminal NPLF motif of the ARF6 guanine nucleotide exchange factor, EFA6B, and promotes its exchange activity in vitro. In cells, a NUMB-EFA6B-ARF6 axis regulates the recycling of the actin regulatory cargo RAC1 and is critical for the formation of CDRs that mark the acquisition of a mesenchymal mode of motility. Consistently, loss of NUMB promotes HGF-induced cell migration and invasion. Thus, NUMB negatively controls membrane protrusions and the acquisition of mesenchymal migratory traits by modulating EFA6B-ARF6 activity.

Original languageEnglish
Pages (from-to)3161-3182
Number of pages22
JournalJournal of Cell Biology
Issue number9
Publication statusPublished - Sep 1 2018


ASJC Scopus subject areas

  • Cell Biology

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