title: Ligand oligomerization state controls Tie2 receptor trafficking and angiopoietin-2-specific responses.
abstract: Angiopoietin 1 (Ang1) is an activating ligand for the endothelial receptor tyrosine kinase Tie2, whereas Ang2 acts as a context-dependent agonist or antagonist that has a destabilizing effect on the vasculature. The molecular mechanisms responsible for the versatile functions of Ang2 are poorly understood. We show here that Ang2, but not Ang1, induces Tie2 translocation to the specific cell-matrix contact sites located at the distal end of focal adhesions. The Ang2-specific Tie2 translocation was associated with distinct Tie2 activation and downstream signals which differed from those of Ang1, and led to impaired cell motility and weak cell-matrix adhesion. We demonstrate that the different oligomeric or multimeric forms of the angiopoietins induce distinct patterns of Tie2 trafficking; the lower oligomerization state of native Ang2 was crucial for the Ang2-specific Tie2 redistribution, whereas multimeric structures of Ang1 and Ang2 induced similar responses. The Ang2-specific Tie2 trafficking to cell-matrix contacts was also dependent on the cell substratum, α2β1-integrin-containing cell-matrix adhesion sites and intact microtubules. Our data indicate that the different subcellular trafficking of Tie2-Ang2 and Tie2-Ang1 complexes generates ligand-specific responses in the angiopoietin-Tie signaling pathway, including modulation of cell-matrix interactions.
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Pietilä
authors.forename: Marjut
authors.initials: M
authors.lastname: Nätynki
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kangas
authors.forename: Kristina H
authors.initials: KH
authors.lastname: Pulkki
authors.forename: Nisha
authors.initials: N
authors.lastname: Limaye
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Pipsa
authors.initials: P
authors.lastname: Saharinen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Lauri
authors.initials: L
authors.lastname: Eklund
mesh_terms: D042683:Angiopoietin-1 / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D021982:Cell-Matrix Junctions / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism; D058449:Intravitreal Injections; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic; D055503:Protein Multimerization; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014822:Vitreous Body / Q000098:blood supply*
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D038982:Integrin alpha2beta1; D011993:Recombinant Fusion Proteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse