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

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...

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Bibliographic Details
Published in:The Journal of cell biology 2018-09, Vol.217 (9), p.3161-3182
Main Authors: 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
Format: Article
Language:English
Subjects:
Actin
ADP-Ribosylation Factor 6
ADP-Ribosylation Factors - metabolism
Cell adhesion & migration
Cell Line, Tumor
Cell migration
Cell Movement - physiology
Cell Polarity
Guanine
Guanine nucleotide exchange factor
Guanine Nucleotide Exchange Factors - metabolism
HeLa Cells
Hepatocyte Growth Factor - metabolism
Humans
Life Sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mesenchyme
Mesoderm - cytology
Mesoderm - metabolism
Molecular modelling
Motility
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
NUMB protein
Platelet-derived growth factor
Platelet-Derived Growth Factor - metabolism
Protein Binding
Protein Domains
Proteins
rac1 GTP-Binding Protein - metabolism
Rac1 protein
Ribonucleotide reductase
RNA Interference
RNA, Small Interfering - genetics
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201802023