Editors' ChoiceChemotaxis

Integrating the Chemotactic Response

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Science Signaling  10 May 2011:
Vol. 4, Issue 172, pp. ec138
DOI: 10.1126/scisignal.4172ec138

Integrins, transmembrane receptors that mediate cell binding to extracellular matrix proteins, act synergistically with growth factor receptors to promote migration of adherent cells toward diffusible growth factors. King et al. used fibroblasts from β1 integrin floxed transgenic mice to explore the mechanism whereby β1 integrin contributes to chemotactic responses to platelet-derived growth factor (PDGF). Although total and cell surface PDGF receptor (PDGFR) abundance of fibroblasts lacking β1 integrin (β1–/– cells) was comparable to that of β1+/+ cells, they failed to migrate toward a PDGF gradient. Ligand binding stimulates the autophosphorylation, internalization, and subsequent degradation or recycling of the PDGFR, and, after exposure to PDGF, PDGFR tyrosine phosphorylation was increased in β1–/– cells compared with β1+/+ cells, whereas ligand internalization and PDGFR degradation were decreased, suggesting impaired endocytosis. The abundance of the endocytic actin nucleating protein N-WASP (neuronal Wiskott-Aldrich syndrome protein) was decreased in β1–/– cells compared with β1+/+ cells; in β1–/– cells, N-WASP also showed increased ubiquitination, and proteasomal inhibition rescued the decrease in N-WASP. Overexpression of WIP (WASP-interacting protein) restored N-WASP abundance and membrane localization in β1–/– cells and partially rescued PDGFR degradation and PDGF internalization, as well as restoring chemotaxis toward PDGF. Moreover, WIP knockdown in β1+/+ cells, which decreased N-WASP abundance, decreased PDGF uptake and impaired chemotaxis toward PDGF. PDGF treatment activated β1 integrin; moreover, fluorescence resonance energy transfer (FRET) analysis revealed that PDGF promoted the association of labeled forms of WIP and N-WASP after β1 integrin activation. Indeed, a dynamic interaction between WIP and N-WASP was apparent in polarized protrusions of cells migrating toward PDGF. PDGF activated Cdc42, a small guanosine triphosphatase implicated in N-WASP activation, and promoted its binding to N-WASP, effects that depended on β1 integrin activation. Defective migration in cells lacking N-WASP was rescued by wild-type N-WASP but not a mutant form unable to bind Cdc42 (but still able to bind WIP). The authors thus conclude that PDGF stimulates β1 integrin activation, leading to assembly of N-WASP complexes with WIP and Cdc42 and N-WASP stabilization, events required for PDGFR endocytosis and fibroblast chemotaxis to PDGF.

S. J. King, D. C. Worth, T. M. E. Scales, J. Monypenny, G. E. Jones, M. Parsons, β1 integrins regulate fibroblast chemotaxis through control of N-WASP stability. EMBO J. 30, 1705–1718 (2011). [PubMed]

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