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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3561-3568.
Prepublished online as a Blood First Edition Paper on January 6, 2005; DOI 10.1182/blood-2004-10-4089.
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Submitted October 27, 2004
Accepted December 31, 2004
Transglutaminase-mediated oligomerization of the fibrin(ogen)  C-domains promotes integrin-dependent cell adhesion and signaling
Alexey M Belkin*, Galina Tsurupa, Evgeny Zemskov, Yuri Veklich, John W Weisel, and Leonid Medved
Department of Biochemistry and Molecular Biology and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
* Corresponding author; email: belkina{at}usa.redcross.org.
Interactions of endothelial cells with fibrin(ogen) are implicated in inflammation, angiogenesis, and wound healing. Cross-linking of the fibrinogen  C-domains with factor XIIIa generates ordered C oligomers mimicking polymeric arrangement of the C-domains in fibrin. These oligomers and those prepared with tissue transglutaminase, were used to establish a mechanism of the C-domain-mediated interaction of fibrin with endothelial cells. Cell adhesion and chemical cross-linking experiments revealed that oligomerization of the C-domains by both transglutaminases significantly increases their RGD-dependent interaction with endothelial V 3, and to a lesser extent with V5 and 51 integrins. The oligomerization promotes integrin clustering, thereby increasing cell adhesion, spreading, formation of prominent peripheral focal contacts, and integrin-mediated activation of FAK and ERK signaling pathways. The enhanced integrin clustering is likely caused by ordered juxtaposition of RGD-containing integrin-binding sites upon oligomerization of the C-domains and increased affinity of these domains for integrins. Our findings provide new insights into the mechanism of the C-domain-mediated interaction of endothelial cells with fibrin and imply its potential involvement in cell migration. They also suggest a new role for transglutaminases in regulation of integrin-mediated adhesion and signaling via covalent modification of integrin ligands.
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