FMNL Formins Boost Lamellipodial Force Generation

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Mar 23

PMID 28327544

Citations 74

Authors

Frieda Kage

Moritz Winterhoff

Vanessa Dimchev

Jan Mueller

Tobias Thalheim

Anika Freise

Stefan Bruhmann

Jana Kollasser

Jennifer Block

Georgi Dimchev

Matthias Geyer

Hans-Joachim Schnittler

Cord Brakebusch

Theresia E B Stradal

Marie-France Carlier

Michael Sixt

Josef Kas

Jan Faix

Klemens Rottner

Affiliations

Soon will be listed here.

Abstract

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.

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References

Cai L, Makhov A, Schafer D, Bear J . Coronin 1B antagonizes cortactin and remodels Arp2/3-containing actin branches in lamellipodia. Cell. 2008; 134(5):828-42. PMC: 2570342. DOI: 10.1016/j.cell.2008.06.054. View

Peng J, Wallar B, Flanders A, Swiatek P, Alberts A . Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42. Curr Biol. 2003; 13(7):534-45. DOI: 10.1016/s0960-9822(03)00170-2. View

Colon-Franco J, Gomez T, Billadeau D . Dynamic remodeling of the actin cytoskeleton by FMNL1γ is required for structural maintenance of the Golgi complex. J Cell Sci. 2011; 124(Pt 18):3118-26. PMC: 3172187. DOI: 10.1242/jcs.083725. View

Bear J, Gertler F . Ena/VASP: towards resolving a pointed controversy at the barbed end. J Cell Sci. 2009; 122(Pt 12):1947-53. PMC: 2723151. DOI: 10.1242/jcs.038125. View

Zhu X, Zeng Y, Guan J, Li Y, Deng Y, Bian X . FMNL2 is a positive regulator of cell motility and metastasis in colorectal carcinoma. J Pathol. 2011; 224(3):377-88. DOI: 10.1002/path.2871. View

Vinson V, De La Cruz E, Higgs H, Pollard T . Interactions of Acanthamoeba profilin with actin and nucleotides bound to actin. Biochemistry. 1998; 37(31):10871-80. DOI: 10.1021/bi980093l. View

Young L, Heimsath E, Higgs H . Cell type-dependent mechanisms for formin-mediated assembly of filopodia. Mol Biol Cell. 2015; 26(25):4646-59. PMC: 4678021. DOI: 10.1091/mbc.E15-09-0626. View

Anderson K, Page C, Swift M, Suraneni P, Janssen M, Pollard T . Nano-scale actin-network characterization of fibroblast cells lacking functional Arp2/3 complex. J Struct Biol. 2016; 197(3):312-321. PMC: 5360490. DOI: 10.1016/j.jsb.2016.12.010. View

Innocenti M, Zucconi A, Disanza A, Frittoli E, Areces L, Steffen A . Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat Cell Biol. 2004; 6(4):319-27. DOI: 10.1038/ncb1105. View

10.

Steffen A, Ladwein M, Dimchev G, Hein A, Schwenkmezger L, Arens S . Rac function is crucial for cell migration but is not required for spreading and focal adhesion formation. J Cell Sci. 2013; 126(Pt 20):4572-88. PMC: 3817791. DOI: 10.1242/jcs.118232. View

11.

Lammers M, Rose R, Scrima A, Wittinghofer A . The regulation of mDia1 by autoinhibition and its release by Rho*GTP. EMBO J. 2005; 24(23):4176-87. PMC: 1356318. DOI: 10.1038/sj.emboj.7600879. View

12.

Kuhn S, Erdmann C, Kage F, Block J, Schwenkmezger L, Steffen A . The structure of FMNL2-Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation. Nat Commun. 2015; 6:7088. PMC: 4432619. DOI: 10.1038/ncomms8088. View

13.

Krause M, Gautreau A . Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat Rev Mol Cell Biol. 2014; 15(9):577-90. DOI: 10.1038/nrm3861. View

14.

Pellegrin S, Mellor H . The Rho family GTPase Rif induces filopodia through mDia2. Curr Biol. 2005; 15(2):129-33. DOI: 10.1016/j.cub.2005.01.011. View

15.

Winkler C, Vinzenz M, Small J, Schmeiser C . Actin filament tracking in electron tomograms of negatively stained lamellipodia using the localized radon transform. J Struct Biol. 2012; 178(1):19-28. DOI: 10.1016/j.jsb.2012.02.011. View

16.

Koestler S, Steffen A, Nemethova M, Winterhoff M, Luo N, Margit Holleboom J . Arp2/3 complex is essential for actin network treadmilling as well as for targeting of capping protein and cofilin. Mol Biol Cell. 2013; 24(18):2861-75. PMC: 3771948. DOI: 10.1091/mbc.E12-12-0857. View

17.

Lai F, Szczodrak M, Block J, Faix J, Breitsprecher D, Mannherz H . Arp2/3 complex interactions and actin network turnover in lamellipodia. EMBO J. 2008; 27(7):982-92. PMC: 2265112. DOI: 10.1038/emboj.2008.34. View

18.

Brunner C, Ehrlicher A, Kohlstrunk B, Knebel D, Kas J, Goegler M . Cell migration through small gaps. Eur Biophys J. 2006; 35(8):713-9. DOI: 10.1007/s00249-006-0079-1. View

19.

Block J, Stradal T, Hanisch J, Geffers R, Kostler S, Urban E . Filopodia formation induced by active mDia2/Drf3. J Microsc. 2008; 231(3):506-17. DOI: 10.1111/j.1365-2818.2008.02063.x. View

20.

Bernstein B, Bamburg J . ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 2010; 20(4):187-95. PMC: 2849908. DOI: 10.1016/j.tcb.2010.01.001. View