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Integrin and receptor tyrosine kinase signalling networks cooperate to regulate various biological functions. The molecular details underlying the integration of both signalling networks remain largely uncharacterized. Here we identify a signalling module composed of a fibronectin–α5β1-integrin–integrin-linked-kinase (ILK) complex that, in concert with epidermal growth factor (EGF) cues, cooperatively controls the formation of transient actin-based circular dorsal ruffles (DRs) in fibroblasts. DR formation depends on the precise spatial activation of Src at focal adhesions by integrin and EGF receptor signals, in an ILK-dependent manner. In a SILAC-based phosphoproteomics screen we identified the tumour-suppressor Cyld as being required for DR formation induced by α5β1 integrin and EGF receptor co-signalling. Furthermore, EGF-induced Cyld tyrosine phosphorylation is controlled by integrin–ILK and Src as a prerequisite for DR formation. This study provides evidence for a novel function of integrin–ILK and EGF signalling crosstalk in mediating Cyld tyrosine phosphorylation and fast actin-based cytoskeletal rearrangements.


  • * Present address: The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Bearsden, Glasgow G611BD, UK

  • Present address: Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany

  • Funding

    This work was supported by the Max Planck Society and the Tiroler Zukunftsstiftung.

  • Supplementary material available online at

  • Accepted September 1, 2011.
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