The long term aim of this project is to understand the physiological control of cytokine signaling pathways that mediate cellular proliferation and differentiation. These pathways are activated inappropriately by cytokines or are otherwise subverted in a wide range of diseases including cancer, autoimmunity and inflammatory and infectious diseases. Previous work funded under this grant using functional genetic screens identified a family of critical negative regulators of cytokine signaling called the supressors of cytokine signaling (SOCS). Gene deletion experiments revealed that SOCS-1 is an essential molecule required to keep in check the potentially lethal effects of endogenous interferon-gamma and biochemical experiments revealed that SOCS-1 interacts with activated JAK kinases and inhibits their activity.
The aims of the present project are: (1) to analyse in gene-deleted mice the unique and redundant physiological roles of three different SOCS proteins (SOCS-1 to - 3). In the case of a lethal phenotype (as for SOCS-1 -/- and SOCS-3-/- mice) tissue-specific, conditional gene deletions or crosses to cytokine-deleted mice will be performed to identify the site of action of the defect. (2) to determine the specificity of different SOCS proteins in inhibiting the actions of different cytokines by performing genetic crosses of mice with different SOCS or cytokine deletions; and (3) to identify the physiological molecular targets that interact with SOCS proteins to mediate their inhibitory effects and determine the biochemical and biological consequences of each interaction. Interacting proteins will be identified by co-association, direct binding and definition of peptide specificity recognition and the quantitative binding affinity of each interaction determined. All analyses based on in vitro biological effects or biochemical interactions will be verified in the whole animal by generating appropriate gene-deleted or -modified mice (e.g. producing a SOCS protein with only one interaction domain deleted) and by appropriate genetic crosses (e.g with mice in which the proposed interaction partner has been deleted). These studies are expected to define physiologically-validated therapeutic targets for the design of molecules that should have therapeutic value in treating diseases associated with the exogenous or endogenous activation of cytokine signaling pathways, especially inflammation, leukemias and other cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Walter and Eliza Hall Institute Medical Research
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VIC, -3052
Nicola, Nicos A; Babon, Jeffrey J (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26:533-44
Babon, Jeffrey J; Varghese, Leila N; Nicola, Nicos A (2014) Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 26:13-9
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Kershaw, Nadia J; Laktyushin, Artem; Nicola, Nicos A et al. (2014) 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 32:1-10
Kedzierski, Lukasz; Linossi, Edmond M; Kolesnik, Tatiana B et al. (2014) Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection. PLoS Pathog 10:e1004134
Varghese, Leila N; Ungureanu, Daniela; Liau, Nicholas P D et al. (2014) Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses. Biochem J 458:395-405
Linossi, Edmond M; Babon, Jeffrey J; Hilton, Douglas J et al. (2013) Suppression of cytokine signaling: the SOCS perspective. Cytokine Growth Factor Rev 24:241-8
Zhang, Jian-Guo; Nicholson, Sandra E (2013) Detection of endogenous SOCS1 and SOCS3 proteins by immunoprecipitation and Western blot analysis. Methods Mol Biol 967:249-59
Babon, Jeffrey J (2013) Quantitative analysis of JAK binding using isothermal titration calorimetry and surface plasmon resonance. Methods Mol Biol 967:57-67
Kershaw, Nadia J; Murphy, James M; Liau, Nicholas P D et al. (2013) SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol 20:469-76

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