Induction of membrane circular dorsal ruffles requires co-signalling of integrin-ILK-complex and EGF receptor

J Cell Sci. 2012 Jan 15;125(Pt 2):435-48. doi: 10.1242/jcs.091652.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane Structures / enzymology
  • Cell Membrane Structures / physiology
  • Cells, Cultured
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Deubiquitinating Enzyme CYLD
  • ErbB Receptors / metabolism*
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Humans
  • Integrin alpha5beta1 / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Signal Transduction*
  • Tyrosine / metabolism

Substances

  • Integrin alpha5beta1
  • Tyrosine
  • integrin-linked kinase
  • ErbB Receptors
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Serine-Threonine Kinases
  • CYLD protein, mouse
  • Deubiquitinating Enzyme CYLD
  • Cysteine Endopeptidases