Dissection of the actin assembly machinery at the lamellipodium tip
Final Report Abstract
Project 2.4 continued worked performed together with Theresia Stradal during the initial funding period that focused on the characterization of Arp2/3-complex actin assembly in the lamellipodium. Lamellipodium protrusion is driven by polymerisation of actin filaments abutting the plasma membrane. Actin filament turnover in the lamellipodium is maintained by continuous generation of novel filaments (nucleation) and capping of existing ones, which stops their growth. Work performed during the first funding phase did shed light on the coordination of the different nanomachineries driving actin filament turnover at the lamellipodium tip. The characterization of Arp2/3-complex actin assembly in the lamellipodium was jointly performed with Theresia Stradal. Work during the second funding period focused mainly on the characterization of the consequences of abrupt Arp2/3 complex inactivation in the lamellipodium. In this project, it was shown that Arp2/3 complex is essential not only for the initiation of lamellipodia, but also for their maintenance. Furthermore, Arp2/3 complex turned out to be upstream of accumulation of seemingly independent lamellipodial regulators, such as capping protein or cofilin. In several collaborative studies branching from these core projects, the ultrastructure in situ of the three-dimensional actin network in lamellipodia as well as structure and function of WAVE-complex subunits were analysed.
Publications
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(2008) Arp2/3 complex interactions and actin network turnover in lamellipodia. EMBO J 27(7):982-92
Lai FP, Szczodrak M, Block J, Faix J, Breitsprecher D, Mannherz HG, Stradal TE, Dunn GA, Small JV, Rottner K
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(2009) Cortactin promotes migration and platelet-derived growth factor-induced actin reorganization by signaling to Rho-GTPases. Mol Biol Cell 20(14):3209-23
Lai FP, Szczodrak M, Oelkers JM, Ladwein M, Acconcia F, Benesch S, Auinger S, Faix J, Small JV, Polo S, Stradal TE, Rottner K
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(2009) F- and G-actin concentrations in lamellipodia of moving cells. PLoS One 4: e4810
Koestler SA, Rottner K, Lai F, Block J, Vinzenz M, Small JV
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(2009) Filopodia: Complex models for simple rods. Int J Biochem Cell Biol 41: 1656-1664
Faix J, Breitsprecher D, Stradal TE, Rottner K
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(2012) FMNL2 drives actin-based protrusion and migration downstream of Cdc42. Curr Biol 22: 1005-1012
Block J, Breitsprecher D, Kuhn S, Winterhoff M, Kage F, Geffers R, Duwe P, Rohn JL, Baum B, Brakebusch C, Geyer M, Stradal TE, Faix J, Rottner K
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(2013) Arp2/3 complex is essential for actin network treadmilling as well as for targeting of capping protein and cofilin. Mol Biol Cell 24: 2861-2875
Koestler SA, Steffen A, Nemethova M, Winterhoff M, Luo N, Holleboom JM, Krupp J, Jacob S, Vinzenz M, Schur F, Schluter K, Gunning PW, Winkler C, Schmeiser C, Faix J, Stradal TE, Small JV, Rottner K
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(2013) Inhibitory signalling to the Arp2/3 complex steers cell migration. Nature
Dang I, Gorelik R, Sousa-Blin C, Derivery E, Guerin C, Linkner J, Nemethova M, Dumortier JG, Giger FA, Chipysheva TA, Ermilova VD, Vacher S, Campanacci V, Herrada I, Planson AG, Fetics S, Henriot V, David V, Oguievetskaia K, Lakisic G, Pierre F, Steffen A, Boyreau A, Peyrieras N, Rottner K, Zinn-Justin S, Cherfils J, Bieche I, Alexandrova AY, David NB, Small JV, Faix J, Blanchoin L, Gautreau A
