Frieda Kage

Dartmouth College

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Klemens Rottner

Technische Universität Braunschweig

Theresia E. B. Stradal

Helmholtz Centre for Infection Research

Anika Steffen

Helmholtz Centre for Infection Research

Matthias Schaks

Helmholtz Centre for Infection Research

Hermann Döring

Helmholtz Centre for Infection Research

Cord Brakebusch

University of Copenhagen

Mathias Müsken

Helmholtz Centre for Infection Research

Thomas Klünemann

Helmholtz Centre for Infection Research

Wulf Blankenfeldt

Helmholtz Centre for Infection Research

Henry N. Higgs

Dartmouth College

Cooperative Institutions

Centre National de la Recherche Scientifique

Helmholtz Centre for Infection Research

Austrian Academy of Sciences

Cancer Research UK Scotland Institute

CeMM Research Center for Molecular Medicine

University of Glasgow

Technische Universität Braunschweig

Medical University of Vienna

Cancer Research UK

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases

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RhoG and Cdc42 can contribute to Rac-dependent lamellipodia formation through WAVE regulatory complex-binding

Small GTPases (2019)

Matthias Schaks Hermann Döring Frieda Kage Anika Steffen Thomas Klünemann

Cell migration frequently involves the formation of lamellipodial protrusions, the initiation of which requires Rac GTPases signalling to heteropentameric WAVE regulatory complex (WRC). While Rac-related RhoG and Cdc42 can potently stimulate lamellipodium formation, so far presumed to occur by upstream signalling to Rac activation, we show here that the latter can be bypassed by RhoG and Cdc42 given that WRC has been artificially activated. This evidence arises from generation of B16-F1 cells simultaneously lacking both Rac GTPases and WRC, followed by reconstitution of lamellipodia formation with specific Rho-GTPase and differentially active WRC variant combinations. We conclude that formation of canonical lamellipodia requires WRC activation through Rac, but can possibly be tuned, in addition, by WRC interactions with RhoG and Cdc42.

Lamellipodium

CDC42

Filopodia

Pseudopodia

10.1080/21541248.2019.1657755

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Citations (16)

Forces generated by lamellipodial actin filament elongation regulate the WAVE complex during cell migration

Nature Cell Biology (2021)

Amine Mehidi Frieda Kage Zeynep Karatas Maureen Cercy Matthias Schaks

Elongation

10.1038/s41556-021-00786-8

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Citations (45)

Nanoscale segregation of actin nucleation and elongation factors determines dendritic spine protrusion

The EMBO Journal (2014)

Anaël Chazeau Amine Mehidi Deepak Nair Jérémie Gautier Cécile Leduc

Elongation

10.15252/embj.201488837

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Citations (137)

Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion

Current Biology (2021)

Stephanie Stahnke Hermann Döring Charly Kusch David J. J. de Gorter Sebastian Dütting

Paxillin

Lamellipodium

Podosome

Pseudopodia

10.1016/j.cub.2021.02.043

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Citations (26)

The structure of FMNL2–Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation

Nature Communications (2015)

Sonja Kühn Constanze Erdmann Frieda Kage Jennifer Block Lisa Schwenkmezger

Abstract Formins are actin polymerization factors that elongate unbranched actin filaments at the barbed end. Rho family GTPases activate Diaphanous-related formins through the relief of an autoregulatory interaction. The crystal structures of the N-terminal domains of human FMNL1 and FMNL2 in complex with active Cdc42 show that Cdc42 mediates contacts with all five armadillo repeats of the formin with specific interactions formed by the Rho-GTPase insert helix. Mutation of three residues within Rac1 results in a gain-of-function mutation for FMNL2 binding and reconstitution of the Cdc42 phenotype in vivo . Dimerization of FMNL1 through a parallel coiled coil segment leads to formation of an umbrella-shaped structure that—together with Cdc42—spans more than 15 nm in diameter. The two interacting FMNL–Cdc42 heterodimers expose six membrane interaction motifs on a convex protein surface, the assembly of which may facilitate actin filament elongation at the leading edge of lamellipodia and filopodia.

CDC42

Filopodia

Lamellipodium

10.1038/ncomms8088

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Citations (75)

Distinct Interaction Sites of Rac GTPase with WAVE Regulatory Complex Have Nonnredundant Functions in Vivo

SSRN Electronic Journal (2018)

Matthias Schaks Shashi Prakash Singh Frieda Kage Peter A. Thomason Thomas Klünemann

Cell migration often involves the formation of sheet‐like lamellipodia, generated by actin filament branching through Arp2/3 complex. In these structures, the latter is activated by WAVE regulatory complex (WRC) downstream of small GTPases of the Rac family. Recent structural studies defined two independent Rac1 binding sites on WRC within the Sra‐1/PIR121 subunit of the pentameric WRC, but the functions of these sites in vivo have remained unknown. Here we used CRISPR/Cas9‐mediated gene disruption of Sra‐1 and its paralogue PIR121 in murine B16‐F1 cells combined with Sra‐1 mutant rescue to dissect the mechanism of WRC activation and the in vivo relevance of distinct Rac binding sites on Sra‐1. We found that the A site, positioned adjacent to the binding region of WAVE‐WCA mediating actin‐ and Arp2/3 complex binding, is the main site for allosteric activation of WRC. In contrast, the D site towards the C‐terminus is dispensable for WRC activation but required for optimal lamellipodium morphology and function. These results were confirmed in evolutionarily distant Dictyostelium amoebas. Moreover, the phenotype seen in D site mutants was recapitulated in Rac1 E31 and F37 mutants , we conclude these residues are important for Rac/D site interaction. Finally, lamellipodia formation was observable even after disruption of both Rac interaction sites in constitutively active WRC, showing Rac interaction is not essential for membrane recruitment. Our data establish that physical interaction with Rac is required for WRC activation, in particular through the A site, but not mandatory for WRC accumulation in the lamellipodium.

10.2139/ssrn.3188452

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Citations (3)

FMNL formins boost lamellipodial force generation

Nature Communications (2017)

Frieda Kage Moritz Winterhoff Vanessa Dimchev Jan Mueller Tobias Thalheim

Migration frequently involves Rac-mediated protrusion of lamellipodia, formed by Arp2/3 complex-dependent branching thought to be crucial for force generation and stability of these networks. The formins FMNL2 and FMNL3 are Cdc42 effectors targeting to the lamellipodium tip and shown here to nucleate and elongate actin filaments with complementary activities in vitro. In migrating B16-F1 melanoma cells, both formins contribute to the velocity of lamellipodium protrusion. Loss of FMNL2/3 function in melanoma cells and fibroblasts reduces lamellipodial width, actin filament density and -bundling, without changing patterns of Arp2/3 complex incorporation. Strikingly, in melanoma cells, FMNL2/3 gene inactivation almost completely abolishes protrusion forces exerted by lamellipodia and modifies their ultrastructural organization. Consistently, CRISPR/Cas-mediated depletion of FMNL2/3 in fibroblasts reduces both migration and capability of cells to move against viscous media. Together, we conclude that force generation in lamellipodia strongly depends on FMNL formin activity, operating in addition to Arp2/3 complex-dependent filament branching.

Formins

10.1038/ncomms14832

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Citations (136)

Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51

Nature Cell Biology (2024)

Ao Liu Frieda Kage Asan F. Abdulkareem Mac Pholo Aguirre-Huamani Gracie Sapp

10.1038/s41556-024-01400-3

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Citations (4)

Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin

Current Biology (2017)

Emma F. Woodham Nikki R. Paul Benjamin J. Tyrrell Heather J. Spence Karthic Swaminathan

The individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large, bulky pseudopods with dynamic actin bursts. Despite assuming an elongated shape usually associated with fast mesenchymal motility, Cdc42 knockout melanoblasts migrated slowly and inefficiently in the epidermis, with nearly static pseudopods. Although much of the basic actin machinery was intact, Cdc42 null cells lacked the ability to polarize their Golgi and coordinate motility systems for efficient movement. Loss of Cdc42 de-coupled three main systems: actin assembly via the formin FMNL2 and Arp2/3, active myosin-II localization, and integrin-based adhesion dynamics.

Pseudopodia

CDC42

10.1016/j.cub.2017.01.033

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Citations (43)

On the relation between filament density, force generation, and protrusion rate in mesenchymal cell motility

Molecular Biology of the Cell (2018)

Setareh Dolati Frieda Kage Jan Mueller Mathias Müsken Marieluise Kirchner

Lamellipodia are flat membrane protrusions formed during mesenchymal motion. Polymerization at the leading edge assembles the actin filament network and generates protrusion force. How this force is supported by the network and how the assembly rate is shared between protrusion and network retrograde flow determines the protrusion rate. We use mathematical modeling to understand experiments changing the F-actin density in lamellipodia of B16-F1 melanoma cells by modulation of Arp2/3 complex activity or knockout of the formins FMNL2 and FMNL3. Cells respond to a reduction of density with a decrease of protrusion velocity, an increase in the ratio of force to filament number, but constant network assembly rate. The relation between protrusion force and tension gradient in the F-actin network and the density dependency of friction, elasticity, and viscosity of the network explain the experimental observations. The formins act as filament nucleators and elongators with differential rates. Modulation of their activity suggests an effect on network assembly rate. Contrary to these expectations, the effect of changes in elongator composition is much weaker than the consequences of the density change. We conclude that the force acting on the leading edge membrane is the force required to drive F-actin network retrograde flow.

Lamellipodium

Leading edge

Pseudopodia

10.1091/mbc.e18-02-0082

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Citations (26)