The alternatively spliced αeC domain of human fibrinogen-420 is a novel ligand for leukocyte integrins αMβ2 and αXβ2

Valeryi K. Lishko, Valentin P. Yakubenko, Kathe M. Hertzberg, Gerd Grieninger, Tatiana P. Ugarova

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The interaction of human plasma fibrinogen with leukocyte integrins αMβ2 (CD11b/CD18, Mac-1) and αXβ2 (CD11c/CD18, p150,95) is an important component of the inflammatory response. Previously, it was demonstrated that binding of fibrinogen to these integrins is mediated γC, the globular C-terminal domain of the γ chain. In this study, evidence was found of another fibrinogen domain that can serve as a ligand for the 2 leukocyte integrins: αEC, a homologous domain that extends the α chains in a recently discovered subclass of fibrinogen known as fibrinogen-420. Recombinant αEC supported strong adhesion and migration of cells expressing αMβ2 and αXβ2 including nonactivated and activated U937 and THP-1 monocytoid cells, and neutrophils. Cells transfected with complementary DNA for these integrins also bound αEC. The specificity of interaction was substantiated by inhibition of cell adhesion with antibodies against αM, αX and β2 subunits. Also, neutrophil inhibitory factor, a specific inhibitor of αMβ2 and αXβ2 function, efficiently blocked cell adhesion to αEC. In αMβ2 and αXβ2, the I domain is the binding site for αEC, since αEC bound to recombinant αM I and αXI domains in a dose-dependent and saturable manner. Synthetic peptides that duplicated sequences γ190 to 202 and γ377 to 395, previously considered putative binding sites in γC, effectively inhibited αMβ2- and αXβ2-mediated adhesion to αEC, suggesting that recognition of αEC by the I domain involves structural features in common with those of γC. These findings identify αEC as a second domain in fibrinogen-420 that binds αMβ2 and αXβ2 and can mediate leukocyte adhesion and migration.

Original languageEnglish (US)
Pages (from-to)2448-2455
Number of pages8
JournalBlood
Volume98
Issue number8
DOIs
StatePublished - Oct 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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