Profilin promotes lamellipodium protrusion by tuning the antagonistic activities of capping protein and VASP
Cell migration frequently employs protrusions termed lamellipodia, constituting the prime model system for generation of branched actin filament networks. Here we utilize genome editing to explore the functional connections between the actin monomer-binding protein profilin (Pfn), the filament nucleating Arp2/3 complex, its co-factor heterodimeric capping protein (CP) and Ena/VASP family polymerases in lamellipodial actin assembly. We show that Pfn counters Ena/VASP but promotes Arp2/3 complex activity, while Ena/VASP and CP mutually antagonize each other. While Pfn promotes Arp2/3 complex activity irrespective of Ena/VASP, sensitivity of CP to Pfn removal vanishes in the absence of Ena/VASP. Our findings establish Pfn as master regulator of Arp2/3 complex-dependent actin network formation, differentially regulating VASP and its antagonizer CP. Mathematical modeling of our data suggest Ena/VASP and CP to compete for recruitment to lamellipodial edges. Our work provides critical insights into the molecular logic of branched actin network assembly in protrusion and force generation.
Authors
- Matthias Schaks (ORCID: https://orcid.org/0000-0001-6362-7909)
- Klemens Rottner (ORCID: https://orcid.org/0000-0003-4244-4198)
- Peter Bieling (ORCID: https://orcid.org/0000-0002-7458-4358)
- Martin Falcke (ORCID: https://orcid.org/0000-0001-7137-1114)
- Sijian Hu
- Jan Faix (ORCID: https://orcid.org/0000-0003-1803-9192)
- Magdalena Miętkowska
- Jonas Scholz (ORCID: https://orcid.org/0009-0000-4789-4249)
- Jessica L. Henty-Ridilla (ORCID: https://orcid.org/0000-0002-7203-8791)
- Zhilun Li
- Sarah Körber (ORCID: https://orcid.org/0000-0002-5077-9345)
- Theresia E. B. Stradal (ORCID: https://orcid.org/0000-0002-0352-9474)
- Marius Karger (ORCID: https://orcid.org/0009-0003-4513-3923)
- Roger Karlsson (ORCID: https://orcid.org/0000-0001-9310-3233)
- Ruth Benavente-Naranjo
- Yubo Tang (ORCID: https://orcid.org/0009-0000-8813-7121)
- Xinqi Jiang (ORCID: https://orcid.org/0009-0008-8492-4898)
- Christopher Lambert
- Julian Kaltenhäuser (ORCID: https://orcid.org/0009-0002-7780-4771)
Institutions
- University of Science and Technology of China (CN)
- University of Helsinki (FI)
- Stockholm University (SE)
- Cal Poly Humboldt (US)
- SUNY Upstate Medical University (US)
- Max Delbrück Center (DE)
- Helsinki Institute of Physics (FI)
- Medizinische Hochschule Hannover (DE)
- Humboldt-Universität zu Berlin (DE)
- MRC Laboratory for Molecular Cell Biology (GB)
- Westerdijk Fungal Biodiversity Institute (NL)
- Helmholtz Centre for Infection Research (DE)
- Max Planck Institute of Molecular Physiology (DE)
- Institute of Molecular Biology and Biophysics (RU)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-16
- DOI
- https://doi.org/10.1038/s41467-026-77694-8
- Primary Topic
- Cellular Mechanics and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- King's College London
- Deutsche Forschungsgemeinschaft
- Carl Tryggers Stiftelse för Vetenskaplig Forskning
- China Scholarship Council
- Rheinische Friedrich-Wilhelms-Universität Bonn
- National Institutes of Health