# Systematic approaches to reveal novel regulatory functions of tyrosine phosphorylation

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2020 · $360,148

## Abstract

Project Summary
Many cell signaling networks rely on tyrosine phosphorylation to convert extracellular cues into cell phenotypic
outcomes. Tyrosine phosphorylation (pTyr) is important to diverse cellular processes and is often implicated in
disease. There has been explosive growth in the identification of pTyr, with 46,000 pTyr sites now known to exist
in the human proteome and we understand the function of only a small percentage of these sites. This work fo-
cuses on a uniquely tyrosine phenomenon of phosphorylation – 25% of pTyr fall within protein domains, which are
central to pTyr-mediated signaling networks. We propose to exploit the fact that protein domains are conserved
both structurally and functionally by focusing on tyrosine phosphorylation that is structurally conserved within do-
mains. The fundamental premise is that the functional effect of pTyr within a specific structural location within a
domain will have the same effect across all domains that share it. This project will specifically address the novel
possibility that the specificity of multiple types of domains for their interacting partners is regulated by tyrosine
phosphorylation occurring within the domain. This work is enabled by integrated computational and experimental
approaches, which can: identify conserved tyrosine phosphorylation, hypothesize effects based on the role of
that conserved tyrosine within domain function, use physiological evidence to understand its involvement in cell
signaling processes, and systematically test pTyr effects on domain function in vitro and within cell signaling net-
works. Focusing on two important interaction domains in cell signaling, this work will likely reveal new paradigms
involving pTyr-mediated signaling, which has broad implications in our basic understanding of cell signaling and
could help identify new therapeutic targets across a broad range of diseases.

## Key facts

- **NIH application ID:** 10029062
- **Project number:** 1R35GM138127-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Kristen M Naegle
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,148
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029062

## Citation

> US National Institutes of Health, RePORTER application 10029062, Systematic approaches to reveal novel regulatory functions of tyrosine phosphorylation (1R35GM138127-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10029062. Licensed CC0.

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