We are interested in how cytokines such as interleukin-6 help orchestrate development of the haematapoietic system. Cytokines control blood cell differentiation by acting as inter-cellular messengers. However their action needs to be tightly controlled in order to prevent proliferative diseases such as leukemia. The proteins responsible for this control include the SOCS (suppressors of cytokine signaling) family. We are interested in understanding the action of the SOCS proteins and other inhibitory molecules at a molecular level.
Australia, The University of Melbourne BSc (Hons), PhD
2012 Burnet Prize, Walter and Eliza Hall Institute
2008 Career Development Award, National Health and Medical Research Council
2017 Servier Industry Grant
2007, 2011, 2014, 2017 Project Grants, NHMRC
2017 Program Grant, NHMRC
2017 Fellowship, NHMRC
2014 Grant-in-aid, Cancer Council Victoria
Kershaw, NJ, Laktyushin, A, et al. Reconstruction of an active SOCS3-based E3 ubiquitin ligase complex in vitro: identification of the active components and JAK2 and gp130 as substrates. Growth Factors. 2014 Feb;32(1):1-10. PMID: 24438103.
Babon, JJ, Varghese, LN, et al. Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol. 2014 Feb;26(1):13-19. PMID: 24418198.
Varghese, LN, Ungureanu, D, et al. Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses. Biochem J. 2013 Dec 19. PMID: 24354892.
Muniz, JRC, Guo, KD, et al. Molecular Architecture of the Ankyrin SOCS Box Family of CuI5-Dependent E3 Ubiquitin Ligases. Journal of Molecular Biology. 2013 Sep 9;425(17):3166-3177. PMID: 23806657.
Kershaw, NJ, Murphy, JM, et al. SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nature Structural & Molecular Biology. 2013 Apr;20(4):469-476. PMID: 23454976.
Babon, JJ and Nicola, NA. The biology and mechanism of action of suppressor of cytokine signaling 3. Growth Factors. 2012 Aug;30(4):207-219. PMID: 22574771.
Babon, JJ, Kershaw, NJ, et al. Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity. 2012 Feb 24;36(2):239-250. PMID: 22342841.
Babon, JJ, Sabo, JK, et al. The SOCS box encodes a hierarchy of affinities for Cullin5: implications for ubiquitin ligase formation and cytokine signalling suppression. J Mol Biol. 2009 Mar 20;387(1):162-174. PMID: 19385048.
Babon, JJ, Sabo, JK, et al. The SOCS box domain of SOCS3: Structure and interaction with the elonginBC-cullin5 ubiquitin ligase. Journal of Molecular Biology. 2008 Sep;381(4):928-940. PMID: WOS:000258971300011.
Babon, JJ, McManus, EJ, et al. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol Cell. 2006 Apr 21;22(2):205-216. PMID: 16630890.
Interleukin-6 (IL6) is a pleiotropic cytokine that has important roles in immunity and inflammation and in some cancers. It can have both pro- and anti-inflammatory activities. Blockade of IL-6 signalling is used to treat both rheumatoid arthritis and Castleman’s Disease. In order to signal, IL6 binds to a specific receptor (IL6-R) found on the surface of target cells. Recently, we have identified a novel protein that controls the levels of this receptor found expressed on the cell surface. This project aims to understand the molecular basis of IL-6 receptor down-regulation and the biological consequences on the immune system. Since the centrality of IL6 to several human diseases has been demonstrated by the approval of IL6 inhibitors for clinical use, understanding the mechanism of inhibition by this novel family of IL6 inhibitors may point to new therapeutic approaches to treating these diseases.