# Regulation of Tie2 activation by homo- and hetero-oligomerization

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $383,156

## Abstract

Abstract
The Tie family of receptor tyrosine kinases (RTKs) are involved in both vascular homeostasis and in
angiogenesis. Both the receptors and their angiopoietin (Ang) ligands are attractive targets for pharmacologic
intervention in cancer, inflammation and other disease states. An impediment to development of therapeutic
agents is the current incomplete understanding of the mechanisms of activation of Tie receptors. Whereas
RTKs such as EGFR, Kit and FGFR are well known to be regulated by growth factor-induced dimerization, for
the Tie receptors, studies to date have failed to reveal the mechanism of ligand-induced receptor activation.
The activating, oligomeric Ang ligands all bind to Tie2, with signaling outcomes that are context dependent and
are modulated by co-receptors including the orphan family member Tie1. We have shown that the extracellular
region (ECR) of Tie2 forms a ligand-independent dimer that is mediated by its membrane-proximal fibronectin
type III (FNIII) domains, and is essential for Tie2 activation in cells. The oligomeric Ang ligands are known to
bind to the membrane distal domains of Tie2. The Tie receptors thus differ from most RTKs in that an
oligomeric ligand regulates an already oligomeric receptor. Whether signaling arises through allosteric
changes in a receptor dimer or the promotion of receptor crosslinking or clustering remains unclear (but is a
focus of our proposal). For several RTKs with immunoglobulin domains in their membrane-proximal regions
(KIT, PDGFR and Fms/CSF1-R), homotypic interactions between membrane-proximal regions are important
for receptor dimerization and activation, and disruption of these interactions by antibody binding or mutation
blocks receptor activation. We propose that interactions involving the membrane-proximal FNIII domains of
Tie receptors can also be targeted therapeutically. Further, we suggest that Tie receptors may serve as a
prototype for the 40% of human RTKs that have membrane-proximal FNIII domains.
 To gain insight into how the oligomeric Ang ligands bind and activated a dimeric RTK, we will use a
combination of structural, biochemical and cellular approaches to address the consequences of binding of
defined, oligomeric Ang ligands to the Tie2 ECR dimer. We will also determine how ligand binding and
signaling are influenced by the presence of Tie1 and the RPTPβ, both of which interact directly with Tie2. Our
overall goal is to build a detailed molecular understanding of how the interactions mediated by the ECR of Tie2
regulate receptor activity, and to exploit this information to develop antibody modulators of Tie receptor
activation. Our specific aims ask three questions:
1. How do angiopoietin ligands regulate Tie2?
2. How do Tie1 and RPTPβ modulate the effects of Ang ligands on Tie2 activity?
3. Can specific antibodies selectively block subsets of Tie2 interactions?

## Key facts

- **NIH application ID:** 9892964
- **Project number:** 5R01CA214704-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** KATHRYN M FERGUSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,156
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892964

## Citation

> US National Institutes of Health, RePORTER application 9892964, Regulation of Tie2 activation by homo- and hetero-oligomerization (5R01CA214704-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9892964. Licensed CC0.

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