Prof James Murphy, Deputy Director | WEHI Researcher Profile

Q: How does the "dead" enzyme MLKL induce cell death

The pseudokinase, MLKL, is the terminal effector in the necroptosis cell death pathway. Our structural studies and development of MLKL-deficient laboratory models have enabled us to greatly advance mechanistic knowledge of this protein. Our ongoing work is directed toward understanding how MLKL kills cells following its activation by the upstream protein kinase, RIPK3, and the role of this pathway in causing inflammatory diseases and cancer. These studies are highly collaborative and draw upon in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics approaches.

Q: The emerging roles of pseudokinases in disease

We have identified allostery, molecular switch, scaffolding and competition functions for pseudokinases from detailed structural and functional characterization. Many pseudokinases remain understudied and are considered members of the “dark kinome”. Ongoing work seeks to define the biological functions of these proteins, how they misfunction in disease, and establish their candidacy as drug targets to counter human diseases, especially inflammatory and proliferative diseases. Our work is highly collaborative, with integration of in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics to dissect their functions.

Q: Structure-function characterisation of the epigenetic regulator, Smchd1

Smchd1 is a poorly understood protein comprising an N-terminal ATPase and C-terminal hinge domain. Our recent studies have sought to understand the biological functions (in collaboration with Prof Marnie Blewitt) and structures (in collaboration with Prof Peter Czabotar) of the component domains with a view to understanding its pleiotropic roles as a tumour suppressor, in X chromosome inactivation and gene imprinting.

About

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.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Prof James Murphy

Chiou S, Horne CR, Patel KM, Preaudet A, Rickard JA, Young SN, Jois A, Garnish SE, Hempel A, Hall C, Hildebrand JM, Kueh AJ, Silke J, Putoczki TL, Hawkins ED, Samson AL, Murphy JM. The kinase domain of RIPK3 tunes its scaffolding functions. Cell Death & Differentiation. 2026;33(8):10.1038/s41418-026-01677-x

Nguyen HM, Khajehali E, Pham V, Scott JW, Dite TA, Dagley LF, Murphy JM, Thompson G, Tobin AB, Thal DM, Christopoulos A, van der Westhuizen ET, Valant C. Low Agonism and Balanced Pathway Modulation Distinguish an M1 Muscarinic Receptor Positive Allosteric Modulator Lacking Cholinergic Adverse Effects. ACS Chemical Neuroscience. 2026;17(14):10.1021/acschemneuro.6c00229

Park EC, Thompson AP, Murphy JM, Liang L-Y, Lucet IS. The multifaceted roles of receptor tyrosine pseudokinases in cellular signalling. Biochemical Society Transactions. 2026;54(6):10.1042/bst20260770

Juliani J, Tran S, Harris TJ, Ellis SL, Al-Ani AH, Wijebandara Y, Patel KM, Young SN, Evangelista M, Baloyan D, Reehorst CM, Nightingale R, Jenkins LJ, De Cruz P, Duszyc K, Kile BT, Yap AS, Mariadason JM, Christensen B, Samson AL, Murphy JM, Fairlie WD, Lee EF. Impact of BECLIN1 haploinsufficiency on goblet cell function and susceptibility to colitis. Cell Death & Disease. 2026;17(1):10.1038/s41419-026-08984-8

Xu H, Sato M, Fernando S, Cochran B, Nankivell V, Tapia Caceres F, Wang Y, Bisht K, Denton K, Nicholls S, murphy J, Bursill C, Rye K-A, Karunakaran D. Abstract Thu076: Partial loss of macrophage Ripk1 drives atheroprotection in Ldlr -/- Mice and is controlled by ApoAI–IL-10-STAT3 anti-inflammatory signaling.Arteriosclerosis Thrombosis and Vascular Biology. 2026;46(Suppl_1):10.1161/atvb.46.suppl_1.thu076

Sato M, Li X, Xu H, Alammar A, Fernando S, Anari M, Dhakal K, Niogret S, Wang Y, Rahman T, Yung Chih C, Nicholls S, Lee R, Mullick A, Drew B, murphy J, Karunakaran D. Abstract Thu075: Therapeutic knockdown of MLKL reduces diet-induced obesity and improves insulin signalling in adipocytes.Arteriosclerosis Thrombosis and Vascular Biology. 2026;46(Suppl_1):10.1161/atvb.46.suppl_1.thu075

Ma X, Vaillant F, Gopal D, Schoffer K, Shojaee F, Pang J, Baldwin CA, Murphy JM, Silke J, Tanzer MC, Visvader JE, Salvamoser R, Vince JE. IAP-based biodegraders can convert necroptosis to apoptosis and eliminate cancer driving protein complexes. Cell Chemical Biology. 2026;33(4):10.1016/j.chembiol.2026.03.005

Murphy JM, Olson AJ. Inspiring discovery through reviews and visualization in biochemistry. Trends in Biochemical Sciences. 2026;51(4):10.1016/j.tibs.2026.01.009

Fernando W, Clucas J, Rizzo A, Singer R, Goode E, Tiu C, Layzell S, Konecnik J, Wilson R, Wicky John S, Jouny S, Guppy N, Boulat V, Mannion J, Goicoechea M, Tan S, Lawson S, Starling C, Elshtein G, Ravindran N, Montgomery AB, Andres-Ejarque R, Allen M, Lumbard S, Wallberg F, Betteridge K, Scrimgeour R, Robertson D, Ward G, Sims M, Smyth T, Samson AL, Murphy JM, Kolarevic Ivankovic D, Arwert EN, Calado DP, Grigoriadis A, Smalley MJ, Melcher A, Haider S, Lawrence T, Roxanis I, Tutt ANJ, Tenev T, Meier P. Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy. Nature Communications. 2026;17(1):10.1038/s41467-026-70133-8

Horne CR, Wang T, Young SN, Dite TA, Nyvall HG, Suresh S, Davies KA, Castro AG, Vaibhav V, Mather LJ, Dagley LF, Belousoff MJ, Manning G, Means AR, Burke JE, Petersen J, Scott JW, Murphy JM. Unconventional binding of calmodulin to CHK2 kinase inhibits catalytic activity. Biochemical Journal. 2025;482(23):10.1042/bcj20253431