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

Abstract

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
Volume217
Issue number9
DOIs
Publication statusPublished - Sep 1 2018

Fingerprint

Recycling
Actins
Guanine Nucleotide Exchange Factors
Cell Movement
Membranes
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Cell Biology

Cite this

A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility. / Zobel, Martina; Disanza, Andrea; Senic-Matuglia, Francesca; Franco, Michel; Colaluca, Ivan Nicola; Confalonieri, Stefano; Bisi, Sara; Barbieri, Elisa; Caldieri, Giusi; Sigismund, Sara; Pece, Salvatore; Chavrier, Philippe; Di Fiore, Pier Paolo; Scita, Giorgio.

In: Journal of Cell Biology, Vol. 217, No. 9, 01.09.2018, p. 3161-3182.

Research output: Contribution to journalArticle

Zobel, Martina ; Disanza, Andrea ; Senic-Matuglia, Francesca ; Franco, Michel ; Colaluca, Ivan Nicola ; Confalonieri, Stefano ; Bisi, Sara ; Barbieri, Elisa ; Caldieri, Giusi ; Sigismund, Sara ; Pece, Salvatore ; Chavrier, Philippe ; Di Fiore, Pier Paolo ; Scita, Giorgio. / A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility. In: Journal of Cell Biology. 2018 ; Vol. 217, No. 9. pp. 3161-3182.
@article{25d8a97a3a5f4184ba764ab0d09b06d8,
title = "A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility",
abstract = "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.",
author = "Martina Zobel and Andrea Disanza and Francesca Senic-Matuglia and Michel Franco and Colaluca, {Ivan Nicola} and Stefano Confalonieri and Sara Bisi and Elisa Barbieri and Giusi Caldieri and Sara Sigismund and Salvatore Pece and Philippe Chavrier and {Di Fiore}, {Pier Paolo} and Giorgio Scita",
year = "2018",
month = "9",
day = "1",
doi = "10.1083/jcb.201802023",
language = "English",
volume = "217",
pages = "3161--3182",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "9",

}

TY - JOUR

T1 - A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

AU - Zobel, Martina

AU - Disanza, Andrea

AU - Senic-Matuglia, Francesca

AU - Franco, Michel

AU - Colaluca, Ivan Nicola

AU - Confalonieri, Stefano

AU - Bisi, Sara

AU - Barbieri, Elisa

AU - Caldieri, Giusi

AU - Sigismund, Sara

AU - Pece, Salvatore

AU - Chavrier, Philippe

AU - Di Fiore, Pier Paolo

AU - Scita, Giorgio

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85054644686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054644686&partnerID=8YFLogxK

U2 - 10.1083/jcb.201802023

DO - 10.1083/jcb.201802023

M3 - Article

AN - SCOPUS:85054644686

VL - 217

SP - 3161

EP - 3182

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 9

ER -