Fibronectin-tissue transglutaminase matrix rescues RGD-impaired celladhesion through syndecan-4 and β integrin co-signaling

Dilek Telci, Zhuo Wang, Xiaoling Li, Elisabetta A.M. Verderio, Martin J. Humphries, Manuela Baccarini, Huveyda Basaga, Martin Griffin

Research output: Contribution to journalArticlepeer-review


Heterotropic association of tissue transglutaminase (TG2) with extracellular matrix-associated fibronectin (FN) can restore the adhesion of fibroblasts when the integrin-mediated direct binding to FN is impaired using RGD-containing peptide. We demonstrate that the compensatory effect of the TG-FN complex in the presence of RGD-containing peptides is mediated by TG2 binding to the heparan sulfate chains of the syndecan-4 cell surface receptor. This binding mediates activation of protein kinase Ca (PKCa) and its subsequent interaction with ß1 integrin since disruption of PKCa binding to ß1 integrins with a cell-permeant competitive peptide inhibits cell adhesion and the associated actin stress fiber formation. Cell signaling by this process leads to the activation of focal adhesion kinase and ERK1/2 mitogen-activated protein kinases. Fibroblasts deficient in Raf-1 do not respond fully to the TG-FN complex unless either the full-length kinase competent Raf-1 or the kinase-inactive domain of Raf-1 is reintroduced, indicating the involvement of the Raf-1 protein in the signaling mechanism. We propose a model for a novel RGD-independent cell adhesion process that could be important during tissue injury and/or remodeling whereby TG-FN binding to syndecan-4 activates PKCa leading to its association with ß1 integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation.
Original languageEnglish
Pages (from-to)20937-20947
Number of pages11
JournalJournal of Biological Chemistry
Issue number30
Publication statusPublished - 25 Jul 2008

Bibliographical note

© 2008 The American Society for Biochemistry and Molecular Biology, Inc.


  • nicotinic acetylcholine receptor
  • nAChR
  • Na
  • K-ATPase functionally
  • skeletal muscle
  • binding
  • nanomolar concentrations
  • electrogenic transport
  • K-ATPase α2 isozyme
  • membrane hyperpolarization
  • neuromuscular transmission
  • muscle excitation


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