Murphy Lab

Our work is focused on understanding how proteins within cells interact, and how genetic mutations that perturb these interactions can cause disease.

We are particularly interested in interactions between proteins involved in cell signalling. The network of signalling proteins within cells can be likened to an electronic circuit. Our research is identifying the missing components in these ‘circuits’ and explaining how diseases are caused by defects in the circuit components.

By understanding how defective signalling causes disease, we aim to develop drugs to control the actions of defective components. In particular we are seeking to understand how signalling defects can lead to a range of diseases, including ischemia-reperfusion injuries, such as stroke and kidney injury, inflammatory bowel disease, muscular dystrophy and cancers.

We aim to understand how changes in our DNA lead to inflammatory diseases in patients with disease. Our work provides detailed insights into the underlying mechanisms that we can build on to develop drugs to counter debilitating diseases, like Crohn’s disease and ulcerative colitis.

Our work has illuminated the molecular mechanism by which the killer protein, MLKL, is activated by the upstream kinase, RIPK3, to induce a pro-inflammatory form of cell death called necroptosis. Using innovative tools and integrative methods, we have defined four critical regulated steps in MLKL’s activation, which we term “checkpoints” in the necroptosis signaling pathway.

More broadly, we have validated pseudokinases, like MLKL, as underappreciated, but critical, signalling molecules throughout nature. Pseudokinases comprise ~10% of our kinome, and through detailed study, we have described diverse functional mechanisms by which pseudokinases function in signalling pathways, and how these functions are disrupted in disease. These studies have unearthed pseudokinases as novel candidates for therapeutic targeting.