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 identi?cation 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 speci?c structural location within a domain will have the same effect across all domains that share it. This project will speci?cally address the novel possibility that the speci?city 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.

Public Health Relevance

This work seeks to challenge our basic understanding of the biochemical networks that are important to how cells make decisions. In addition to improving our basic understanding, this work could help to open new avenues for the treatment of diabetes, in?ammation, and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM138127-01
Application #
10029062
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Brazhnik, Paul
Project Start
2020-09-15
Project End
2025-06-30
Budget Start
2020-09-15
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904