β1 integrins regulate fibroblast chemotaxis through control of N-WASP stability

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 beta 1 integrins are required both for fibroblast chemotaxis towards platelet-derived growth factor (PDGF) and growth factor-induced dorsal ruffling. Mechanistically, we show that b1 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 b1 integrin within newly assembled actin-rich membrane ruffles. Active b1 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 b1 integrins. This represents a novel mechanism by which integrins cooperate with growth factor receptors to promote localised signalling and directed cell motility. The EMBO Journal (2011) 30, 1705-1718. doi:10.1038/emboj.2011.82; Published online 22 March 2011