RGD-independent cell adhesion via a tissue transglutaminase-fibronectin matrix promotes fibronectin fibril deposition and requires syndecan-4/2 and α5β1 integrin co-signaling

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Abstract

Fibronectin (FN) deposition mediated by fibroblasts is an important process in matrix remodeling and wound healing. By monitoring the deposition of soluble biotinylated FN, we show that the stress-induced TG-FN matrix, a matrix complex of tissue transglutaminase (TG2) with its high affinity binding partner FN, can increase both exogenous and cellular FN deposition and also restore it when cell adhesion is interrupted via the presence of RGD-containing peptides. This mechanism does not require the transamidase activity of TG2 but is activated through an RGD-independent adhesion process requiring a heterocomplex of TG2 and FN and is mediated by a syndecan-4 and ß1 integrin co-signaling pathway. By using a5 null cells, ß1 integrin functional blocking antibody, and a a5ß1 integrin targeting peptide A5-1, we demonstrate that the a5 and ß1 integrins are essential for TG-FN to compensate RGD-induced loss of cell adhesion and FN deposition. The importance of syndecan-2 in this process was shown using targeting siRNAs, which abolished the compensation effect of TG-FN on the RGD-induced loss of cell adhesion, resulting in disruption of actin skeleton formation and FN deposition. Unlike syndecan-4, syndecan-2 does not interact directly with TG2 but acts as a downstream effector in regulating actin cytoskeleton organization through the ROCK pathway. We demonstrate that PKCa is likely to be the important link between syndecan-4 and syndecan-2 signaling and that TG2 is the functional component of the TG-FN heterocomplex in mediating cell adhesion via its direct interaction with heparan sulfate chains.

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Original languageEnglish
Pages (from-to)40212-40129
Number of pages18
JournalJournal of Biological Chemistry
Volume285
Issue number51
Early online date7 Oct 2010
DOIs
Publication statusPublished - 17 Dec 2010

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© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

    Keywords

  • actins, animals, CHO cells, cell adhesion, cricetinae, cricetulus, cytoskeleton, extracellular matrix, fibronectins, GTP-binding proteins, heparitin sulfate, humans, integrin alpha5beta1, mice, mutant strains mice, oligopeptides, protein kinase C-alpha, Small Interfering RNA, signal transduction, syndecan-2, syndecan-4, transglutaminases, rho-associated kinases

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