Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands

Mol Cell. 2010 Mar 12;37(5):643-55. doi: 10.1016/j.molcel.2010.02.007.


The Tie family of endothelial-specific receptor tyrosine kinases is essential for cell proliferation, migration, and survival during angiogenesis. Despite considerable similarity, experiments with Tie1- or Tie2-deficient mice highlight distinct functions for these receptors in vivo. The Tie2 receptor is further unique with respect to its structurally homologous ligands. Angiopoietin-2 and -3 can function as agonists or antagonists; angiopoietin-1 and -4 are constitutive agonists. To address the role of Tie1 in angiopoietin-mediated Tie2 signaling and determine the basis for the behavior of the individual angiopoietins, we used an in vivo FRET-based proximity assay to monitor Tie1 and -2 localization and association. We provide evidence for Tie1-Tie2 complex formation on the cell surface and identify molecular surface areas essential for receptor-receptor recognition. We further demonstrate that the Tie1-Tie2 interactions are dynamic, inhibitory, and differentially modulated by angiopoietin-1 and -2. Based on the available data, we propose a unified model for angiopoietin-induced Tie2 signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1 / metabolism*
  • Angiopoietin-2 / metabolism*
  • Cell Line
  • Cell Membrane / enzymology
  • Endothelial Cells / enzymology*
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Ligands
  • Models, Molecular
  • Mutation
  • Protein Conformation
  • Protein Multimerization
  • Protein Structure, Tertiary
  • RNA Interference
  • Receptor Cross-Talk
  • Receptor, TIE-1 / chemistry
  • Receptor, TIE-1 / genetics
  • Receptor, TIE-1 / metabolism*
  • Receptor, TIE-2 / chemistry
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • Structure-Activity Relationship
  • Time Factors
  • Transfection


  • Angiopoietin-1
  • Angiopoietin-2
  • Ligands
  • Recombinant Fusion Proteins
  • Receptor, TIE-1
  • Receptor, TIE-2