Ligand oligomerization state controls Tie2 receptor trafficking and Angiopoietin-2 ligand-specific responses

Abstract

SummaryAngiopoietin 1 (Ang1) is an activating ligand for the endothelial receptor tyrosine kinase Tie2, whereas Ang2 acts as a contextdependent 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, a2b1-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.

Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1–induced collective directional migration and angiogenic sprouting

“…Interestingly, it has been shown previously that after activation, Tie2 forms clusters at cell-cell contacts in confluent cells where it regulates endothelial cell permeability and also has been shown to localize at the trailing edge of migrating cells. 13,44 We now show that during collective migration, Tie2 clusters form at the leading edge of leader cells but do not colocalize with adherens junction proteins or PKC, similar to what has been observed at cell junctions. 13 This suggests that distinct signaling events must emerge from Tie2 to promote the formation of ␤-catenin/PKC complexes at cell junctions and for the localization of polarity and adherens junction proteins at the leading edge.…”

Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization

“…We show that Tie1/Tie2 heterodimerization may involve interactions between the Fn3 domains, but it is not clear how Tie1 interacts with the arrays of Tie2 homodimers in trans or how angiopoietins bridge Tie2 association across EC-EC junctions. The context-dependent differences in angiopoietin-activated Tie2 signaling pathways may depend on differences in other subcellular protein constituents, such as integrins in the ECM contacts and VE-PTP in EC-EC contacts (10,13,19,47). Further structural and functional investigation is required to understand how Tie1 acts to modulate the effects of Ang1 and Ang2 on Tie2 and the mechanism of Ang2 antagonism in the Tie2 trans association.…”

Erythrocytic Stage-dependent Regulation of Oligomerization of Plasmodium Ribosomal Protein P2

“…For instance, angiopoietin 2 modulates the endothelial receptor tyrosine kinase Tie2 and induces Tie2 translocation to the specific cell-matrix contact sites located at the distal end of focal adhesions. It is reported that the different oligomeric/multimeric forms of the angiopoietins cause induction of distinct patterns of Tie2 trafficking (68). Similarly phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (69).…”