Matthias Krause
King's College London, UK
Actin cytoskeleton regulation at the intersection of endocytosis, Wnt signalling, and cell migration
How cells internalise surface receptors controls everything from embryonic development to tissue maintenance, yet the molecular machinery driving this remains incompletely understood. Canonical Wnt signalling is essential for both, and while Wnt receptor internalisation is required for pathway activation, how this uptake occurs has been controversial. Two endocytic routes exist: classical Clathrin-Mediated Endocytosis (CME), and the more recently discovered Fast Endophilin-Mediated Endocytosis (FEME) — a rapid, clathrin-independent mechanism operating at the leading edge of migrating cells. In the first of two stories, we show that Wnt3a simultaneously triggers both CME and FEME of Wnt receptors, even at low ligand concentrations sufficient for pathway activation, resolving previous controversies. This efficient endocytosis is specifically facilitated by the actin regulator Mena — identifying it as a key and unexpected mediator of Wnt receptor complex internalisation and Wnt activation.
In a second story, we address how actin dynamics are regulated during FEME itself — a question that has remained open since the pathway was discovered. NHSL1, a Nance-Horan Syndrome protein family member, controls cell protrusions and migration, but also localises to vesicular compartments where its function has been unknown. We show that NHSL1 and its uncharacterised family member NHSL2 cooperate with endophilin A2 and the actin regulators Ena/VASP to coordinate actin polymerisation and membrane invagination, thereby driving FEME. Together, these two stories reveal how actin cytoskeleton regulators operate at the interface of endocytosis, cell signalling, and migration, opening new questions about how cytoskeletal dynamics are coupled to receptor trafficking in development and disease.
Selected references
- Narayan KB, James HP, Cope J, Mondal S, Baeyens L, Milano F, Zheng J, Krause M, Baumgart T. Endophilin-lamellipodin-VASP, key components in fast endophilin-mediated endocytosis, control actin polymerization within liquid-like condensates. J Biol Chem. 2025 Dec;301(12):110834
- Law AL, Jalal S, Pallett T, Mosis F, Guni A, Brayford S, Yolland L, Marcotti S, Levitt JA, Poland SP, Rowe-Sampson M, Jandke A, Köchl R, Pula G, Ameer-Beg SM, Stramer BM, Krause M. Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration. Nat Commun. 2021 Sep 28;12(1):5687
- Vehlow A, Soong D, Vizcay-Barrena G, Bodo C, Law AL, Perera U, Krause M. Endophilin, Lamellipodin, and Mena cooperate to regulate F-actin-dependent EGF-receptor endocytosis. EMBO J. 2013 Oct 16;32(20):2722-34