Tyrosine phosphorylation can be thought of as a biochemical switch. When a phosphate group is added to tyrosine, an amino acid found in proteins, it changes the way the protein functions and alters its interaction with other proteins within the cell. Because tyrosine phosphorylation is connected to such processes as cell differentiation, cell division and cell migration, these changes are fundamental to both the development and stability of living organisms. Accordingly, when tyrosine phosphorylation goes awry, it can lead to diseases like cancer, diabetes and neurodegenerative disorders.

As Associate Professor Kristen Naegle points out, making sense of tyrosine phosphorylation is an immense project. Thanks to improvements in measurement technologies, we now know that there are 46,000 of phosphotyrosines in the human proteome, that’s more than twice the number of protein encoding genes in the human genome.

Kristen Naegle

"I am very excited to be part of a department whose faculty members routinely use data- and computationally driven approaches to gain insight into biological problems. This is relatively unusual."

Kristen Naegle joined the department in Fall 2018

Making the Move from St. Louis to Charlottesville

At Washington University in St. Louis, Naegle established a reputation for pairing computational and molecular techniques to predict and test the role of tyrosine phosphorylation on proteins and cellular networks. For instance, she analyzed data from a previously published study that isolated phosphorylation in a HER2-positive breast cell line and a normal breast cell line. She found small changes in signaling dynamics produced very large changes in the relationships between groups of signaling molecules that could lead to metastasis. Experimental data was consistent with this finding.

Naegle brings these strategies for cell signaling to UVA where she joins faculty members applying similar approaches to issues of inflammation, infectious disease, cardiac disease and cancer. “I am very excited to be working with a group of people doing cutting-edge work in quantitative approaches to signaling,” she says. “And to be part of a department whose faculty members routinely use data- and computationally driven approaches to gain insight into biological problems. This is relatively unusual.”

Approaching Tyrosine Phosphorylation as a Design Problem

As a researcher, Naegle takes an eclectic approach. “In my lab, we are not tied to a specific technique or methodology,” she says. “Our overriding interest is tackling the challenge of tyrosine phosphorylation, and we cross disciplines as necessary to achieve this goal.” Naegle and her team regularly tap evolution, machine learning, statistics, mechanistic modeling, biochemistry and cell biology in their work. In essence, she approaches her work as a design problem, putting together from a variety of sources the information and tools needed to test her hypotheses.

As an educator, Naegle feels that being part of a lab that draws its inspiration from different perspectives and disciplines is particularly beneficial to her students. “It is important to learn early on to be wide-ranging in your thinking,” she says.

Welcoming the Full Range of Perspectives

Social inclusion is also important to her. As a researcher and teacher, Naegle is alert to building a diverse environment where everyone feels welcome. “I have committed myself to trying to understand stereotype threats,” she says, referring to a situational predicament in which people underperform, relative to their own ability, as a result of belonging to a group that is negatively stereotyped in that particular task. “I try to do everything I can to mitigate them, whether I’m in the classroom, the lab, or sitting down with undergraduate advisees. I feel it is my responsibility as an educator.”

Naegle joins the department this fall as Associate Professor of BME with courtesy appointments in Computer Science and the Center for Public Health Genomics.

Dr. Naegle’s External Funding Snapshot

NIH R21 212726 A molecular toolkit for the production of tyrosine phosphorylated proteins (PI)

The major goal of this project is to develop a molecular system to produce phosphorylated proteins in a recombinant E. coli system. The model system is to study the effect of phosphorylation on SH2 domains.

NIH R21 231853 Inferring kinase activity profiles from phosphoproteomic data (PI)

The goal of this project is to develop graph and Bayesian algorithmic approaches to convert phosphoproteomic data into a kinase activity profile. Algorithmic approaches will be tested and tailored by application to existing phosphoproteomic data with known kinase activities. Patient-specific kinase activity profiles will be generated to identify patient patterns and possible points of therapeutic intervention.