Tie1-Tie2 Interactions Mediate Functional Differences between Angiopoietin Ligands

Abstract

SUMMARY The endothelial specific receptor tyrosine kinase Tie2, and the orphan receptor tyrosine kinase, Tie1, are essential for endothelial cell proliferation, migration, and survival during angiogenesis. Despite their considerable similarity, experiments with Tie1 or Tie2 deficient mice highlight distinct functions for these two receptors in vivo. However, Tie1 cooperates with Tie2 during Angiopoietin signaling, demonstrating a degree of functional overlap between the two receptor-systems. Tie2 is further unique among receptor tyrosine kinases with respect to its structurally homologous ligands. Angiopoietin-2 and -3 can function as agonists or antagonists depending upon the local environment, while Angiopoietin-1 and -4, are constitutive agonists. To address the role of Tie1 in Angiopoietin-mediated Tie2 signaling, and determine the basis for the unique behavior of the individual Angiopoietins, we used an in vivo FRET-based proximity assay to monitor Tie1 and Tie2 localization and association in the presence and absence of ligands. Here, we provide direct evidence for Tie1-Tie2 complex formation on the endothelial 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, thereby providing a discrete molecular mechanism for the observed variations in Angiopoietin function. Based upon the available data, we propose a unified model for Angiopoietin-induced Tie2 signaling which highlights the essential role of Tie1 in vascular homeostasis.

Structural basis for angiopoietin-1–mediated signaling initiation

“…Thus, these substitutions have little effect on the ligand-receptor-binding interface. The individual angiopoietins exert different biological effects on Tie2-expressing cells as a function of their unique abilities to influence the heterodimeric association of Tie1 and Tie2 on the cell surface (15). It is not unexpected, therefore, that the overall architecture and receptor-ligand interactions are largely conserved between the two structures.…”

“…Indeed, all angiopoietins exist primarily as tetramers, hexamers, and higherorder oligomers in solution. Nonetheless, chimeric Ang ligands illustrate that only the highly conserved receptor-binding fibrinogen domain is necessary and sufficient for their unique functional signaling characteristics (13)(14)(15).…”

“…Indeed, Tie1 and Tie2 form a complex on the endothelial cell surface that inhibits Tie2 signaling (15). The Tie1/Tie2 interactions are predominantly electrostatic in nature and are selectively modulated by the Ang ligands.…”

A peptide from the extracellular region of the synaptic protein α Neurexin stimulates angiogenesis and the vascular specific tyrosine kinase Tie2

“…Although other instances of peptide activators of signaling pathways are known, in the case of Tie2, another 7aa ligand has been identified with inhibitory effects [7]. One hypothesis is that the latter peptide may function by inhibiting Tie2 dimerization [8] while BbcA2 could relieve the receptor from some inhibitory interactions, of which the most plausible is the one with the strictly related, orphan receptor Tie1 [9], or that with NRXN, shown above. The idea that the interaction between Tie2 and NRXN is inhibitory (i.e.…”

TIE-ing off atherosclerosis

“…There is also evidence that TIE1 and TIE2 interact in the cell. [6][7][8] TIE2 binds the family of angiopoietin growth factors to induce angiogenesis. As a result, at least four companies have active programs aimed at blocking TIE2 in cancer.…”