FMNL2 drives actin-based protrusion and migration downstream of Cdc42

Jennifer Block; Dennis Breitsprecher; Sonja Kühn; Moritz Winterhoff; Frieda Kage; Robert Geffers; Patrick Duwe; Jennifer L Rohn; Buzz Baum; Cord Brakebusch; Matthias Geyer; Theresia E B Stradal; Jan Faix; Klemens Rottner

doi:10.1016/j.cub.2012.03.064

FMNL2 drives actin-based protrusion and migration downstream of Cdc42

Jennifer Block, Dennis Breitsprecher, Sonja Kühn, Moritz Winterhoff, Frieda Kage, Robert Geffers, Patrick Duwe, Jennifer L Rohn, Buzz Baum, Cord Brakebusch, Matthias Geyer, Theresia E B Stradal, Jan Faix, Klemens Rottner

Nutritional Immunology

133 Citations (Scopus)

Abstract

Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE [1]. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex [2]. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2 [3], accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia.

Original language	English
Journal	Current Biology
Volume	22
Issue number	11
Pages (from-to)	1005-12
Number of pages	8
ISSN	0960-9822
DOIs	https://doi.org/10.1016/j.cub.2012.03.064
Publication status	Published - 5 Jun 2012

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10.1016/j.cub.2012.03.064

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@article{660779485d39464da19750689fc7b761,

title = "FMNL2 drives actin-based protrusion and migration downstream of Cdc42",

abstract = "Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE [1]. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex [2]. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2 [3], accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia.",

author = "Jennifer Block and Dennis Breitsprecher and Sonja K{\"u}hn and Moritz Winterhoff and Frieda Kage and Robert Geffers and Patrick Duwe and Rohn, {Jennifer L} and Buzz Baum and Cord Brakebusch and Matthias Geyer and Stradal, {Theresia E B} and Jan Faix and Klemens Rottner",

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T1 - FMNL2 drives actin-based protrusion and migration downstream of Cdc42

AU - Block, Jennifer

AU - Breitsprecher, Dennis

AU - Kühn, Sonja

AU - Winterhoff, Moritz

AU - Kage, Frieda

AU - Geffers, Robert

AU - Duwe, Patrick

AU - Rohn, Jennifer L

AU - Baum, Buzz

AU - Brakebusch, Cord

AU - Geyer, Matthias

AU - Stradal, Theresia E B

AU - Faix, Jan

AU - Rottner, Klemens

PY - 2012/6/5

Y1 - 2012/6/5

N2 - Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE [1]. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex [2]. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2 [3], accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia.

AB - Cell migration entails protrusion of lamellipodia, densely packed networks of actin filaments at the cell front. Filaments are generated by nucleation, likely mediated by Arp2/3 complex and its activator Scar/WAVE [1]. It is unclear whether formins contribute to lamellipodial actin filament nucleation or serve as elongators of filaments nucleated by Arp2/3 complex [2]. Here we show that the Diaphanous-related formin FMNL2, also known as FRL3 or FHOD2 [3], accumulates at lamellipodia and filopodia tips. FMNL2 is cotranslationally modified by myristoylation and regulated by interaction with the Rho-guanosine triphosphatase Cdc42. Abolition of myristoylation or Cdc42 binding interferes with proper FMNL2 activation, constituting an essential prerequisite for subcellular targeting. In vitro, C-terminal FMNL2 drives elongation rather than nucleation of actin filaments in the presence of profilin. In addition, filament ends generated by Arp2/3-mediated branching are captured and efficiently elongated by the formin. Consistent with these biochemical properties, RNAi-mediated silencing of FMNL2 expression decreases the rate of lamellipodia protrusion and, accordingly, the efficiency of cell migration. Our data establish that the FMNL subfamily member FMNL2 is a novel elongation factor of actin filaments that constitutes the first Cdc42 effector promoting cell migration and actin polymerization at the tips of lamellipodia.

U2 - 10.1016/j.cub.2012.03.064

DO - 10.1016/j.cub.2012.03.064

M3 - Journal article

C2 - 22608513

SN - 0960-9822

VL - 22

SP - 1005

EP - 1012

JO - Current Biology

JF - Current Biology

IS - 11

ER -

FMNL2 drives actin-based protrusion and migration downstream of Cdc42

Abstract

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