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.

A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility / M. Zobel, A. Disanza, F. Senic-Matuglia, M. Franco, I.N. Colaluca, S. Confalonieri, S. Bisi, E. Barbieri, G. Caldieri, S. Sigismund, S. Pece, P. Chavrier, P.P. Di Fiore, G. Scita. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 217:9(2018 Sep), pp. jcb.201802023.3161-jcb.201802023.3182. [10.1083/jcb.201802023]

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

Caldieri, Giusi;Sigismund, Sara;Pece, Salvatore;Di Fiore, Pier Paolo;Scita, Giorgio
2018-09

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.
Settore MED/04 - Patologia Generale
Settore BIO/13 - Biologia Applicata
THE ENDOCYTIC AND CYTOSKELETAL MATRIX IN THE PLASTICITY OF TUMOR CELL INVASION AND MIGRATION
gen-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/584695
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