The Eps8/IRSp53/VASP Network Differentially Controls Actin Capping and Bundling in Filopodia Formation

Abstract

There is a body of literature that describes the geometry and the physics of filopodia using either stochastic models or partial differential equations and elasticity and coarse-grained theory. Comparatively, there is a paucity of models focusing on the regulation of the network of proteins that control the formation of different actin structures. Using a combination of in-vivo and in-vitro experiments together with a system of ordinary differential equations, we focused on a small number of well-characterized, interacting molecules involved in actin-dependent filopodia formation: the actin remodeler Eps8, whose capping and bundling activities are a function of its ligands, Abi-1 and IRSp53, respectively; VASP and Capping Protein (CP), which exert antagonistic functions in controlling filament elongation. The model emphasizes the essential role of complexes that contain the membrane deforming protein IRSp53, in the process of filopodia initiation. This model accurately accounted for all observations, including a seemingly paradoxical result whereby genetic removal of Eps8 reduced filopodia in HeLa, but increased them in hippocampal neurons, and generated quantitative predictions, which were experimentally verified. The model further permitted us to explain how filopodia are generated in different cellular contexts, depending on the dynamic interaction established by Eps8, IRSp53 and VASP with actin filaments, thus revealing an unexpected plasticity of the signaling network that governs the multifunctional activities of its components in the formation of filopodia.

SH2B1 and IRSp53 Proteins Promote the Formation of Dendrites and Dendritic Branches

“…An IRSp53-interacting protein is Eps8 (epidermal growth factor receptor kinase substrate 8). Eps8 can cap barbed ends of actin filaments when binding to Abi-1, whereas the association of Eps8 with IRSp53 induces filopodium formation by cross-linking actin filaments (30,35,36). These findings suggest that Eps8 can induce or inhibit the filopodium formation depending on its binding proteins.…”

Time to Decide? Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis

“…As in the agent-based model [5,32] filopodia extension and retraction are dependent on [VEGF] and they are modeled in a non-spatial manner by directly capturing the positive feedback between the VEGF ligand (V) and filopodia (filo) mediated VEGF sensing: where n represents the cooperativity in F-actin polymerization and filopodia formation (i.e. a cooperative action in n molecules of F-actin filaments leading to filopodia formation) [33]. Previous studies have shown cooperativity between at least two pathways downstream of VEGFR2 activation leading to F-actin polymerization [34].…”

The inverse BAR-domain protein IBARa drives membrane remodelling to control osmoregulation, phagocytosis and cytokinesis

“…3D). Owing to its localization in filopodia tips and the possible involvement of the I-BAR protein IRSp53 in filopodia formation (Millard et al, 2005;Vaggi et al, 2011), we quantified the total number of filopodia in randomly migrating IBARa-null and WT cells using phase-contrast microscopy. However, and consistent with a recent report (Veltman et al, 2011), we could not find a significant difference; both cell lines formed about six filopodia on average (Fig.…”

“…Previous studies have suggested that I-BAR proteins regulate the formation of actin protrusions through interactions with membranes, actin and other cytoskeletal regulators, for instance as described for IRSp53 with VASP (Vaggi et al, 2011), or the Diaphanous-related formin mDia1 and the Scar/ WAVE-complex subunit WAVE2 (Goh et al, 2011). In addition, pathogens such as enterohaemorrhagic Escherichia coli (EHEC) use these interactions to recruit the actin-assembly machinery for the formation of actin pedestals (de Groot et al, 2011).…”