Characterization of the molecular interplay between VASP, formins and their accessory proteins during filopodium formation
Zusammenfassung der Projektergebnisse
Filopodia are highly dynamic spiky cell surface protrusions found in most cell types. They are comprised of parallel actin filaments compacted into dense bundles and grow by actin monomer incorporation at their tips. Filopodia are considered important sensory organelles, for instance in guidance of neuronal growth cones in response to environmental signals or the fusion of sheets of epithelial tissues during morphogenesis. In addition, they serve as precursors of adhesion sites, stress fibers and dendritic spines, and abundant filopodia are a characteristic feature of invasive cancer cells linking filopodia to cell migration and invasiveness. Despite their biological significance, however, our knowledge of their molecular composition and precise regulation has remained incomplete. It was thus essential to elucidate the interplay of involved proteins, determine their specific contributions and dissect associated signaling pathways. As shown previously by our and other laboratories, Ena/VASP proteins and formins are critical players in filopodium assembly although their specific contribution was controversially discussed. Therefore, our aim was the detailed characterization of actin polymerization by VASP, formins and accessory proteins in this process to better understand the fundamental principles and mechanisms of filopodia formation at the molecular level. The published results of our studies provide detailed insights in the molecular mechanisms supporting VASP and formin-mediated actin assembly processes, formin localization signals, the role of formins in filopodium formation and lamellipodium protrusion as well as the role of cofilin in filopodium retraction Together, these results do substantially increase our understanding of the mechanisms underlying the formation of actin-based cellular protrusions and cell motility.
Projektbezogene Publikationen (Auswahl)
- (2006). Staying in shape with formins. Dev. Cell. 10, 693-706
Faix J, and Grosse R
(Siehe online unter https://doi.org/10.1016/j.devcel.2006.05.001) - (2008). Arp2/3 complex interactions and actin network turnover in lamellipodia. EMBO J. 27, 982-992
Lai FP, Szczodrak M, Block J, Faix J, Breitsprecher D, Mannherz HG, Stradal TE, Dunn GA, Small JV, Rottner K
(Siehe online unter https://doi.org/10.1038/emboj.2008.34) - (2008). Clustering of VASP actively drives processive, WH2 domain-mediated actin filament elongation. EMBO J. 27, 2943-2954
Breitsprecher D, Kiesewetter AK, Linkner J, Urbanke C, Resch GP, Small JV, Faix J
(Siehe online unter https://doi.org/10.1038/emboj.2008.211) - (2008). Filopodia formation induced by active mDia2/Drf3. J. Microsc. 231, 506-517
Block J, Stradal TE, Hänisch J, Geffers R, Köstler SA, Urban E, Small JV, Rottner K, Faix J
(Siehe online unter https://doi.org/10.1111/j.1365-2818.2008.02063.x) - (2009). Analysis of actin assembly by in vitro TIRF microscopy. Methods Mol. Biol. 571, 401-415
Breitsprecher D, Kiesewetter AK, Linkner J, Faix J
(Siehe online unter https://doi.org/10.1007/978-1-60761-198-1_27) - (2009). Cortactin promotes migration and platelet-derived growth factor-induced actin reorganization by signaling to Rho-GTPases. Mol. Biol. Cell. 20, 3209-3223
Lai FP, Szczodrak M, Oelkers JM, Ladwein M, Acconcia F, Benesch S, Auinger S, Faix J, Small JV, Polo S, Stradal TE, Rottner K
(Siehe online unter https://doi.org/10.1091/mbc.e08-12-1180) - (2009). Filopodia: Complex models for simple rods. Int. J. Biochem. Cell Biol. 41, 1656-1664
Faix J, Breitsprecher D, Stradal TE, Rottner K
(Siehe online unter https://doi.org/10.1016/j.biocel.2009.02.012) - (2010). Phospholipids regulate localization and activity of mDia1 formin. Eur. J. Cell Biol. 89, 723-732
Ramalingam N, Zhao H, Breitsprecher D, Lappalainen P, Faix J, Schleicher M
(Siehe online unter https://doi.org/10.1016/j.ejcb.2010.06.001) - (2011). Cofilin cooperates with fascin to disassemble filopodial actin filaments. J. Cell Sci. 124, 3305-3318
Breitsprecher D, Koestler SA, Chizhov I, Nemethova M, Mueller J, Goode BL, Small JV, Rottner K, Faix J
(Siehe online unter https://doi.org/10.1242/jcs.086934) - (2011). Molecular mechanism of Ena/VASP-mediated actin-filament elongation. EMBO J. 30, 456-467
Breitsprecher D, Kiesewetter AK, Linkner J, Vinzenz M, Stradal TE, Small JV, Curth U, Dickinson RB, Faix J
(Siehe online unter https://doi.org/10.1038/emboj.2010.348) - (2011). Structural biochemistry of nuclear actin-related proteins 4 and 8 reveals their interaction with actin. EMBO J. 30, 2153-2166
Fenn S, Breitsprecher D, Gerhold CB, Witte G, Faix J, Hopfner KP
(Siehe online unter https://doi.org/10.1038/emboj.2011.118) - (2012). A dual role for Rac1 GTPases in the regulation of cell motility. J. Cell Sci. 125, 387-398
Filić V, Marinović M, Faix J, Weber I
(Siehe online unter https://doi.org/10.1242/jcs.089680) - (2012). FMNL2 drives actin-based protrusion and migration downstream of Cdc42. Curr. Biol. 22, 1005-1012
Block J, Breitsprecher D, Kühn S, Winterhoff M, Kage F, Geffers R, Duwe P, Rohn JL, Baum B, Brakebusch C, Geyer M, Stradal TE, Faix J, Rottner K
(Siehe online unter https://doi.org/10.1016/j.cub.2012.03.064) - (2013). The application of the Cre-loxP system for generating multiple knock-out and knock-in targeted loci. Methods Mol. Biol. 983, 249-267
Faix J, Linkner J, Nordholz B, Platt JL, Liao XH, Kimmel AR
(Siehe online unter https://doi.org/10.1007/978-1-62703-302-2_13)
