title: 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.
authors.affiliation: IFOM Foundation, Institute FIRC of Molecular Oncology, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Vaggi
authors.forename: Andrea
authors.initials: A
authors.lastname: Disanza
authors.forename: Francesca
authors.initials: F
authors.lastname: Milanesi
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Menna
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.forename: Nir S
authors.initials: NS
authors.lastname: Gov
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciliberto
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology; D006651:Histocytochemistry; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000502:physiology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C119539:BAIAP2 protein, human; D015815:Cell Adhesion Molecules; C489989:EPS8 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein