Fibronectin-tissue transglutaminase matrix rescues RGD-impaired cell adhesion through syndecan-4 and beta1 integrin co-signaling.
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 Calpha (PKCalpha) and its subsequent interaction with beta(1) integrin since disruption of PKCalpha binding to beta(1) 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 PKCalpha leading to its association with beta(1) integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation.
Telci
Dilek
D
School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom.
Wang
Zhuo
Z
Li
Xiaoling
X
Verderio
Elisabetta A M
EA
Humphries
Martin J
MJ
Baccarini
Manuela
M
Basaga
Huveyda
H
Griffin
Martin
M
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D005353:Fibronectins / Q000737:chemistry*; D019204:GTP-Binding Proteins / Q000737:chemistry*; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry*; D020935:MAP Kinase Signaling System; D051379:Mice; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051571:Protein Kinase C-alpha / Q000378:metabolism; D053671:Syndecan-4 / Q000737:chemistry*; D011503:Transglutaminases / Q000737:chemistry*
D005353:Fibronectins; D019012:Integrin beta1; D053671:Syndecan-4; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051571:Protein Kinase C-alpha; D019204:GTP-Binding Proteins