The Walter and Eliza Hall Institute of Medical Research

Dr James Murphy

Details

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Division: Molecular Medicine

Research Overview

All mature, functional blood cells in the human body arise from common stem cells (haematopoietic stem cells; HSCs) following the instructions conveyed by a class of proteins called cytokines. Cytokines provide essential cues to instruct HSCs and progenitor cells to proliferate, survive, differentiate or self-renew by binding to, and activating, cognate receptors present on the surface of these cells.

As an Australian Research Council Future Fellow in the Babon laboratory, my research is focused towards understanding the molecular details of two distinct settings in which protein-protein interactions control blood cell formation:

1. Cytokine binding to their cognate receptors on the surface of blood cells.
2. Inside the cell, where a sophisticated network of signaling proteins dictates cellular responses, such as proliferation and differentiation, after cytokine receptor activation.

Obtaining a comprehensive understanding of the molecular details of these processes using biochemical, structural, biophysical and proteomic techniques is an important step towards identifying novel targets for the development of effective treatments to counter devastating diseases of the blood, such as bone marrow failure and myeloproliferative neoplasms.

Research Projects

1. Understanding the molecular mechanisms by which the pseudokinase domain-containing proteins, the Janus kinases and Mlkl, regulate blood cell production
2. The mechanism of activation of the receptors for IL-3, IL-5 and GM-CSF
3. The molecular basis of how naturally-occurring mutations within the thrombopoietin receptor, c Mpl, cause Chronic Amegakaryocytic Thrombocytopenia (CAMT)

Major Publications

1. Murphy, J.M., Korzhnev, D.M., Ceccarelli, D.F., Briant, D.J., Zarrine-Afsar, A., Sicheri, F., Kay, L.E. and Pawson, T. (2007). Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain. Proc. Natl Acad. Sci. USA, 104, 14336-14341. PMID: 17726107
2. Murphy, J.M., Hansen, D.F., Wiesner, S., Muhandiram, D.R., Borg, M., Smith, M.J., Sicheri, F., Kay, L.E., Forman-Kay, J.D. & Pawson, T. (2009) Structural studies of FF domains of the transcription factor CA150 provide insights into the organization of FF domain tandem arrays. J. Mol. Biol., 393, 409-24. PMID: 19715701
3. Carr, P.D., Gustin, S.E., Church, A.P., Murphy, J.M., Ford, S.C., Mann, D.A., Woltring, D.M., Walker, I., Ollis, D.L. and Young, I.G. (2001) Structure of the complete extracellular domain of the common β-subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration. Cell, 104, 291-300. PMID: 11207369
4. Murphy, J.M., Ford, S.C., Wiedemann, U.M., Carr, P.D., Ollis, D.L. & Young I.G. (2003) A novel functional epitope formed by domains 1 and 4 of the human common β-subunit is involved in receptor activation by granulocyte-macrophage colony-stimulating factor and interleukin-5. J. Biol. Chem., 278, 10572-10577. PMID: 12525483
5. Kauppi, M.*, Murphy, J.M.*, deGraaf, C., Hyland, C.D., Greig, K.T., Metcalf, D., Hilton, A.A., Nicola, N.A., Kile, B.T., Hilton, D.J. and Alexander, W.S. (2008) Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl-/- mice. Blood, 112, 3148-3153. PMID: 18684867 (* denotes equal contribution)

 

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Staff Supervision

PhD student: Leila Varghese MA BSc(Hons) Melb (Co-supervised with Professor Doug Hilton)

Research assistant: Sam Young BSc BMus(Hons) ANU

Research assistant: Kelan Chen BSc (Hons) Melb (Co-supervised with Dr Marnie Blewitt)

 

Contact details

James M Murphy

Cancer and Haematology Division

Walter and Eliza Hall Institute of Medical Research

1G Royal Parade

Parkville, VIC 3052, Australia

 

Email: .(JavaScript must be enabled to view this email address)

Tel: +61 3 9345 2407

Fax: +61 3 9347 0852