We study the mechanisms that allow living cells to sense and respond to external signals. Cell signaling networks are highly interconnected, with signaling proteins often shared by multiple pathways. We seek to understand how signaling proteins are directed to specific targets and how cells prevent inappropriate crosstalk between pathways. Our model systems are the Wnt and PKA signaling networks, which are involved in human cell growth, differentiation, metabolism, and disease. Understanding the underlying mechanisms for specificity may allow us to design therapeutics that precisely target specific functions without affecting other connected pathways.

Our previous work has focused on scaffold proteins, which assemble multi-protein signaling complexes. We have identified new mechanisms used by scaffold proteins to direct kinase activity to the appropriate target, using a combination of quantitative biochemical approaches and cell culture studies. Current projects focus on the relationship between scaffold protein structure and function, how cells dynamically regulate scaffold protein activity, the effects of phase separation on kinase reactivity, and role of scaffold-associated phosphatases in signal processing.

The 3D structure of eukaryotic genomes plays a central role in gene regulation, and aberrant structures are now recognized to affect a wide range of diseases. However, few approaches have been developed to correct aberrant chromatin loops and positioning within the nucleus. We seek to develop methods to efficiently engineer chromatin loops using CRISPR-Cas systems that target either genomic DNA or RNA.

In collaboration with the Baker lab at UW, we developed a CRISPR Co-LOCKR switch that senses whether the complex is bound to DNA. This switching function is an important step towards efficient DNA loop formation, and current projects are directed towards implementing this system in human cells and evaluating the functional effects on gene regulation.