Journal
JOURNAL OF CELL BIOLOGY
Volume 217, Issue 9, Pages 3161-3182Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201802023
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG-18621, IG-18988, MCO 10.000, IG-11904]
- Italian Ministry of University and Scientific Research
- International Association for Cancer Research [AICR-14-0335]
- European Research Council (Advanced-ERC) [268836]
- Italian Ministry of Health [RF-2013-02358446]
- AIRC fellowship
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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.
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