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J Cell Sci. 2015 Oct 15;128(20):3796-810. doi: 10.1242/jcs.176768. Epub 2015 Sep 8.

Initiation of lamellipodia and ruffles involves cooperation between mDia1 and the Arp2/3 complex.

Author information

1
Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
2
Division of Cell Biology I, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
3
Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands m.innocenti@nki.nl.

Abstract

Protrusion of lamellipodia and ruffles requires polymerization of branched actin filaments by the Arp2/3 complex. Although regulation of Arp2/3 complex activity has been extensively investigated, the mechanism of initiation of lamellipodia and ruffles remains poorly understood. Here, we show that mDia1 acts in concert with the Arp2/3 complex to promote initiation of lamellipodia and ruffles. We find that mDia1 is an epidermal growth factor (EGF)-regulated actin nucleator involved in membrane ruffling using a combination of knockdown and rescue experiments. At the molecular level, mDia1 polymerizes linear actin filaments, activating the Arp2/3 complex, and localizes within nascent and mature membrane ruffles. We employ functional complementation experiments and optogenetics to show that mDia1 cooperates with the Arp2/3 complex in initiating lamellipodia and ruffles. Finally, we show that genetic and pharmacological interference with this cooperation hampers ruffling and cell migration. Thus, we propose that the lamellipodium- and ruffle-initiating machinery consists of two actin nucleators that act sequentially to regulate membrane protrusion and cell migration.

KEYWORDS:

Actin; Arp2/3; Cell migration; Lamellipodia; Ruffles; mDia1

PMID:
26349808
DOI:
10.1242/jcs.176768
[Indexed for MEDLINE]
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