title: β1 integrins regulate fibroblast chemotaxis through control of N-WASP stability.
abstract: Chemotactic migration of fibroblasts towards growth factors, such as during development and wound healing, requires precise spatial coordination of receptor signalling. However, the mechanisms regulating this remain poorly understood. Here, we demonstrate that β1 integrins are required both for fibroblast chemotaxis towards platelet-derived growth factor (PDGF) and growth factor-induced dorsal ruffling. Mechanistically, we show that β1 integrin stabilises and spatially regulates the actin nucleating endocytic protein neuronal Wiskott–Aldrich syndrome protein (N-WASP) to facilitate PDGF receptor traffic and directed motility. Furthermore, we show that in intact cells, PDGF binding leads to rapid activation of β1 integrin within newly assembled actin-rich membrane ruffles. Active β1 in turn controls assembly of N-WASP complexes with both Cdc42 and WASP-interacting protein (WIP), the latter of which acts to stabilise the N-WASP. Both of these protein complexes are required for PDGF internalisation and fibroblast chemotaxis downstream of β1 integrins. This represents a novel mechanism by which integrins cooperate with growth factor receptors to promote localised signalling and directed cell motility.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunts House, Guys Campus, London, UK.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: King
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Worth
authors.forename: Timothy M E
authors.initials: TM
authors.lastname: Scales
authors.forename: James
authors.initials: J
authors.lastname: Monypenny
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
mesh_terms: D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D002633:Chemotaxis / Q000502:physiology*; D004705:Endocytosis; D005347:Fibroblasts / Q000502:physiology*; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D055786:Gene Knockout Techniques; D047468:Immunoprecipitation; D019012:Integrin beta1 / Q000378:metabolism*; D016086:Lentivirus; D051379:Mice; D041681:NIH 3T3 Cells; D009841:Oligonucleotides / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D009841:Oligonucleotides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D000077214:Becaplermin