Scar/WAVE drives actin protrusions independently of its VCA domain using proline-rich domains.

Autor:	Buracco S; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK. Electronic address: simona.buracco@cea.fr., Döring H; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany; Department of Cell Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany., Engelbart S; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany; Department of Cell Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany., Singh SP; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Paschke P; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Whitelaw J; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Thomason PA; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Paul NR; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Tweedy L; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH, UK., Lilla S; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., McGarry L; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Corbyn R; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK., Claydon S; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH, UK., Mietkowska M; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany; Department of Cell Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany., Machesky LM; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH, UK., Rottner K; Division of Molecular Cell Biology, Zoological Institute, Technische Universität Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany; Department of Cell Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany; Braunschweig Integrated Centre of Systems Biology (BRICS), 38106 Braunschweig, Germany., Insall RH; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1QH, UK. Electronic address: r.insall@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Current biology : CB [Curr Biol] 2024 Oct 07; Vol. 34 (19), pp. 4436-4451.e9. Date of Electronic Publication: 2024 Sep 26.
DOI:	10.1016/j.cub.2024.08.013
Abstrakt:	Cell migration requires the constant modification of cellular shape by reorganization of the actin cytoskeleton. Fine-tuning of this process is critical to ensure new actin filaments are formed only at specific times and in defined regions of the cell. The Scar/WAVE complex is the main catalyst of pseudopod and lamellipodium formation during cell migration. It is a pentameric complex highly conserved through eukaryotic evolution and composed of Scar/WAVE, Abi, Nap1/NCKAP1, Pir121/CYFIP, and HSPC300/Brk1. Its function is usually attributed to activation of the Arp2/3 complex through Scar/WAVE's VCA domain, while other parts of the complex are expected to mediate spatial-temporal regulation and have no direct role in actin polymerization. Here, we show in both B16-F1 mouse melanoma and Dictyostelium discoideum cells that Scar/WAVE without its VCA domain still induces the formation of morphologically normal, actin-rich protrusions, extending at comparable speeds despite a drastic reduction of Arp2/3 recruitment. However, the proline-rich regions in Scar/WAVE and Abi subunits are essential, though either is sufficient for the generation of actin protrusions in B16-F1 cells. We further demonstrate that N-WASP can compensate for the absence of Scar/WAVE's VCA domain and induce lamellipodia formation, but it still requires an intact WAVE complex, even if without its VCA domain. We conclude that the Scar/WAVE complex does more than directly activating Arp2/3, with proline-rich domains playing a central role in promoting actin protrusions. This implies a broader function for the Scar/WAVE complex, concentrating and simultaneously activating many actin-regulating proteins as a lamellipodium-producing core. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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