# Structural Mechanism of Activation and Modulation of Tie2-mediated Angiogenesis

> **NIH NIH F31** · FRED HUTCHINSON CANCER CENTER · 2024 · $44,249

## Abstract

PROJECT SUMMARY
The cardiovascular system is an essential organ key for development. This highly efficient network of
vasculature structures constantly undergoes expansion and trimming to maintain vessel homeostasis.
Angiogenesis – the budding of new vasculature structures from preexisting vessel systems, is one of the
primary processes contributing to network expansion. Multiple cellular receptors function together to ensure
successful proliferation and motility of endothelial cells for angiogenesis. One of these receptors is Tie2, a
receptor tyrosine kinase (RTK) expressed exclusively on the endothelial cell surface. Tie2's primary role, upon
binding to angiopoietin-1 (Ang-1), is to initiate and maintain tight cell-cell junctions across the endothelial
monolayer. Like other RTKs, Tie2's proposed activation pathway involves the dimerization of the receptors to
propagate a signal across the cell membrane to phosphorylate downstream targets. While the role of Tie2 in
angiogenesis is clear, little is known about the structural changes that Tie2 undergoes that allow for
dimerization. The Ang-1 binding site is distant from the proposed dimerization site. Therefore, information must
travel across multiple domains, and there is currently no mechanism for this transduction. In addition, our
understanding of cell signaling pathways has been described as most straightforward possible, often rendering
them as exclusively linear with a single ligand and receptor. However, within the cellular context, proteins and
ligands are constantly engaging with other signaling pathways in addition to their own. Integrins, a membrane
receptor that has a role in cellular adhesion and motility, have been observed to engage with Tie2 on the
cellular level. But the molecular details remain elusive. Therefore, a structural investigation into Tie2's
activation and modulation with angiopoietin and integrin would contribute to a more complete picture of Tie2
biology. To this end, I will combine cutting-edge structural biology techniques with traditional cellular biology to
dissect these structural changes in Tie2. My goals are to elucidate the molecular mechanism of Tie2
dimerization and the receptor cross-talk that occurs with integrin α5β1. I have designed experiments with
two specific aims to understand how Tie2 is structurally impacted by angiopoietin-1 and integrin α5β1. Aim 1
will examine and describe the impact of Ang-1 binding on the full-length Tie2 receptor using cryogenic electron
microscopy (cryoEM) and cell-based assays. The results from this aim will push the limits of our understanding
of Tie2's structural architecture and ligand-induced dimerization of RTKs. Aim 2 will determine the structural
role of integrin α5β1 in modulating Tie2's signaling axis. I will use a combination of cryoEM and Förster
resonance energy transfer to identify the key residues of this receptor-crosstalk. Results from this aim will shed
light on the functional importance of receptor cross...

## Key facts

- **NIH application ID:** 10903539
- **Project number:** 1F31HL174166-01
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Adam Nguyen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,249
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903539

## Citation

> US National Institutes of Health, RePORTER application 10903539, Structural Mechanism of Activation and Modulation of Tie2-mediated Angiogenesis (1F31HL174166-01). Retrieved via AI Analytics 2026-07-28 from https://api.ai-analytics.org/grant/nih/10903539. Licensed CC0.

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