Modulation of integrin antagonist signaling by ligand binding of the heparin-binding domain of vitronectin to the αVβ3 integrin

Laura A. Maile, Ariel W. Aday, Walker H. Busby, Ravi Sanghani, Umadevi Veluvolu, David R. Clemmons

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The interaction between the arginine glycine and aspartic acid motif (RGD) of integrin ligands such as vitronectin and the integrin receptor αVβ3 in mediating cell attachment has been well described. Similarly, the ability of disintegrins, small RGD containing peptides, to inhibit cell attachment and other cellular processes has also been studied extensively. Recently, we characterized a second site of interaction between vitronectin and its integrin partner. We determined that amino acids within the heparin-binding domain of vitronectin bind to a cysteine loop (C-loop) region of β3 and that this interaction is required for the positive effects of αVβ3 ligand occupancy on IGF-I signaling in smooth muscle cells. In this study we examine the signaling events activated following ligand binding of disintegrins to the αVβ3 and the ability of these signals to be regulated by binding of the heparin-binding domain of vitronectin. We demonstrate that disintegrin ligand binding activates a series of events including the sequential activation of the tyrosine kinases c-Src and Syk. This leads to the activation of calpain and the cleavage of the β3 cytoplasmic tail. Addition of vitronectin or a peptide homologous to the heparin-binding domain inhibited activation of this pathway. Our results suggest that the signaling events that occur following ligand binding to the αVβ3 integrin reflects a balance between the effects mediated through the RGD binding site interaction and the effects mediated by the heparin binding site interaction and that for intact vitronectin the effect of the heparin-binding domain predominates.

Original languageEnglish (US)
Pages (from-to)437-446
Number of pages10
JournalJournal of Cellular Biochemistry
Volume105
Issue number2
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Keywords

  • Echistatin
  • Integrin
  • Vitronectin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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