My laboratory studies how lesser known protein kinases and their catalytically-dead cousins, the pseudokinases, convey signals within cells, and how defects in signalling can lead to disease.
My lab is the most prolific in the study of the pseudokinase, Mixed lineage kinase domain-like (MLKL), which is the terminal effector in the necroptosis cell death pathway. MLKL’s pseudokinase domain acts as a molecular switch that can be tripped by phosphorylation by the upstream kinase, RIPK3, to induce MLKL assembly into higher order structures and permeabilization of the plasma membrane to kill cells. A key focus of our work is understanding the triggers and regulators of MLKL activation, and precisely how MLKL permeabilises the plasma membrane to cause a cell’s demise.
The bulk of pseudokinases and about one-third of kinases are considered “dark” because they are understudied. We have used the lessons learned from studying MLKL for 15 years as a template to shine a light on the functions dark kinases and pseudokinases using an integrated approach. We use protein structure (X-ray crystallography, cryo-EM, cryo-ET, NMR spectroscopy, scattering, structural mass spectrometry), biochemistry, interactomics, phosphoproteomics, microscopy, generation of tools such as antibodies and chemical probes, CRISPR editing, animal models and studies of human biopsies to better understand protein function and the molecular bases of disease. Thus far, our studies of dark kinases and pseudokinase have unearthed novel regulatory mechanisms; dark kinases are a treasure trove for expanding fundamental knowledge, and represent exciting new drug targets for treatment of cancers, inflammatory diseases and developmental disorders.
Precisely how dark kinases and pseudokinases contribute to development and disease is currently poorly-understood. We have drawn knowledge from patients’ genomes to assign functions of (pseudo)kinases in physiology for the first time. Furthermore, over the past 4 years, have studied the biopsies donated by patients with inflammatory bowel disease to understand how hyperactive signalling pathways can lead to disease.