title: Induction of membrane circular dorsal ruffles requires co-signalling of integrin-ILK-complex and EGF receptor.
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.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried,  Germany.
authors.forename: S Babak
authors.initials: SB
authors.lastname: Azimifar
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Böttcher
authors.forename: Sara
authors.initials: S
authors.lastname: Zanivan
authors.forename: Carsten
authors.initials: C
authors.lastname: Grashoff
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Legate
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D021961:Cell Membrane Structures / Q000201:enzymology / Q000502:physiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D066246:ErbB Receptors; D039081:Integrin alpha5beta1; D017346:Protein Serine-Threonine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D014443:Tyrosine; D000099200:Scaffold Protein ILK; C511601:CYLD protein, mouse