Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands.
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.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, 1101 East Marshall Street, Richmond, VA 23298, USA.
Tom C M
TC
Seegar
Becca
B
Eller
Dorothea
D
Tzvetkova-Robev
Momchil V
MV
Kolev
Scott C
SC
Henderson
Dimitar B
DB
Nikolov
William A
WA
Barton
D042683:Angiopoietin-1 / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D020239:Receptor Cross-Talk; D042810:Receptor, TIE-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D008024:Ligands; D011993:Recombinant Fusion Proteins; D042810:Receptor, TIE-1; D042787:Receptor, TIE-2