# Role of spectrin signaling complex in angiogenesis

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $309,374

## Abstract

Defective angiogenesis underlies the pathogenesis of over 50 malignant, ischemic and inflammatory diseases.
While current antagonists of VEGF signaling have a wide range of therapeutic applications, most of these
treatments fail to provide long-term efficacy due to acquired resistance and toxicities. Overcoming these
clinical challenges will therefore require addressing a number of critical aspects of VEGF signaling that are
very much unclear. VEGFR2 is the principal driver of sprouting angiogenesis as its membrane trafficking
controls the specificity, duration and amplitude of many, if not most, of the VEGF-induced signaling pathways.
But unlike the molecular basis of VEGFR2 tyrosine phosphorylation that transduces receptor signaling, how its
membrane trafficking and turnover are spatiotemporally coordinated by various serine/threonine kinases,
chaperones and ubiquitin ligases remain poorly understood. In fact, although PKCs have been long recognized
as key mediators of VEGFR2 degradation, it is still unclear whether PKCs directly or indirectly promote
serine/threonine phosphorylation-induced turnover. Here our work supports an exciting new mechanism by
which VEGFR2 stability is regulated through a novel membrane-based signaling complex. In preliminary
studies, we discovered that IV-spectrin, a large membrane cytoskeletal scaffolding protein characterized only
in the nervous system and heart, is expressed in vascular endothelial cells (ECs) to act as a critical negative
regulator of angiogenesis. IV-spectrin dysfunction in newborn mice and zebrafish embryos produce debilitating
hypersprouting vessels in part due to abnormally high levels of VEGF/VEGFR2 signaling and dramatically
elevated number of tip cells. Our data strongly suggest that IV-spectrin functions as a crucial signaling
platform by which VEGFR2 is targeted for degradation through direct CaMKII-induced phosphorylation of novel
serine/threonine sites. Based on our findings, we hypothesize that the IV-spectrin/CaMKII signaling complex
regulates VEGFR2 phosphorylation, membrane trafficking and turnover to suppress VEGF signaling and tip
cell phenotype during sprouting angiogenesis. Two aims are proposed to test this hypothesis: 1) Define IV-
spectrin-based mechanisms of VEGF signaling during sprouting angiogenesis; 2) Establish the role of IV-
spectrin in endothelial tip and stalk cell specification. Collectively, results from these studies will address a
crucial question in VEGFR signaling through the characterization of a novel IV-spectrin signaling complex, and
identify new vascular targets in failed long-term VEGF-related therapies.

## Key facts

- **NIH application ID:** 10061619
- **Project number:** 5R01GM128055-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Nam Y Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $309,374
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061619

## Citation

> US National Institutes of Health, RePORTER application 10061619, Role of spectrin signaling complex in angiogenesis (5R01GM128055-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10061619. Licensed CC0.

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