When a cytokine binds to its cognate receptor on the outside of the cell, it initiates a signalling cascade on the inside of the cell through a family tyrosine kinases known as the JAKs (Janus Kinases). In turn this activates the STAT family of transcriptional activators, providing a new set of instructions for how a cell should behave. The JAK/STAT pathway is important in many biological processes, including growth and development, hematopoiesis, immunity and inflammation, and aberrant JAK/STAT signalling can lead to diseases such as chronic inflammatory disease and cancer.
We are studying this signalling system both from the outside (cytokine:receptor interactions) and the inside (JAK and proteins that regulate JAK function) of the cell. The Kershaw Lab combines structural biology (X-ray crystallography and cryo-EM) with detailed mechanistic biochemistry and protein chemistry to study these processes, with the view that a detailed mechanistic understanding of protein function will reveal new opportunities for drug design.
We currently have three main objectives:
England, University of Oxford, MChem (Hons), 2000
England, University of Oxford, PhD, 2004
2022-2024, Grant-in-Aid: A new therapy for the treatment of Myeloproliferative Diseases (Babon, Alexander, Kershaw, Brouwer), Cancer Council Victoria
2017-2020, Project grant: The JAK/STAT pathway in health and disease (Babon, Ng, Kershaw), NHMRC
2014-2016, Project grant: Lamin B1, a new anti-cancer target (Lessenne, Kershaw, Kavallaris), NHMRC
2014-2016, Grant-in-Aid: The role of SOCS1 in inflammatory disease and cancer (Babon, Kershaw), Cancer Council Victoria
1. Linossi E, Li K, Veggiani G, Tan C, Dehkhoda F, Hockings C, Calleja D, Keating N, Feltham R, Brooks A, Li S, Sidhu S, Babon JJ, Kershaw NJ*, Nicholson SE*. A novel exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nat Commun. 2021. PMID: 34857742 *Joint corresponding author
2. Morris R, Zhang YY, Ellyard J, Vinuesa C, Murphy JJ, Laktyushin A, Kershaw NJ*, Babon JJ*. Structural and functional analysis of target recognition by the lymphocyte adaptor protein LNK. Nat Commun. 2021. PMID: 34671038 *Joint corresponding author
3. Liau NPD, Laktyushin A, Lucet IS, Murphy JM, Yao S, Whitlock E, Callaghan K, Nicola NA, Kershaw NJ*, Babon JJ*. The molecular basis of JAK/STAT inhibition by SOCS1. Nat Commun. 2018. PMID: 29674694 *Joint corresponding author
4. Kershaw NJ, Church NL, Griffin MD, Luo CS, Adams TE, Burgess AW, Notch ligand delta-like1: X-ray crystal structure and binding affinity. Biochem J. 2015. PMID: 25715738
5. Kershaw NJ, Murphy JM, Liau NP, Varghese LN, Laktyushin A, Whitlock EL, Lucet IS, Nicola NA, Babon JJ. SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol. 2013. PMID: 23454976
1. Morris, R, Kershaw NJ, Babon JJ, The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018. PMID: 30267440
2. Kershaw NJ, Murphy JM, Lucet IS, Nicola NA, Babon JJ., Regulation of Janus kinases by SOCS proteins. Biochem Soc Tran. 2013. PMID: 23863176
The cytokine Thrombopoietin (Tpo) controls the maintenance of blood stem cells as well as the numbers of platelet in the blood. Clinically, excessive signalling through the molecule that recognises Tpo (the Thrombopoietin Receptor) causes a type of blood cancer called myeloproliferative disease.
The architecture of TpoR is distinct from any other cytokine receptor and there is a complete lack of structural data for it. We have developed a recombinant expression system for Tpo and TpoR, which interact readily and we are using crystallography and CryoEM to solve the structure of the TpoR:TpoR complex. We are also using our unique reagents and structural information to developing novel strategies for inhibiting excessive TpoR signalling, with the aim of generating new treatments for myeloproliferative disease. This work is in collaboration with the Babon Lab (WEHI).
The Suppressors of Cytokine Signalling (SOCS) have long been studied at WEHI for their role in negative regulation of cytokine signalling. The Kershaw and Babon Labs have made a significant contribution to basic research in this area, solving the first structures of SOCS1 as the first structures of SOCS1 and SOCS3 bound to the JAK kinase domain. More recently, with the advent of immunotherapy as an exciting treatment option for cancer, inhibiting the SOCS proteins provides a possible route to boost the efficacy of current immunotherapy approaches. We are studying the mechanism of SOCS proteins and other negative regulators of cytokine signaling such as LNK and PTP1B. This work is in collaboration with the Babon Lab (WEHI).
T cells are a critical part of a healthy immune system, and T-cell activation is one of several key events required to successfully mount an immune response. Soluble CTLA4 proteins block T cell activation, and are already in use as therapeutics for rheumatoid arthritis and organ transplant rejection (e.g Abatacept), but recent publications from several groups indicate the mode of action of current CTLA4-based therapeutics may be more complex that initially thought.
We are exploring novel CTLA4-fusions and their potential as immunomodulatory therapeutics. This project involves rational design of CTLA4 variants with altered immunomodulatory activity, and structural studies on the mode of binding with target proteins, to allow further refinement as therapeutics as well as elucidation of the mode of action. This work is in collaboration with Associate Professor Ross Dickins (Monash).
Project resource: Monash University research project: Novel immunosuppressive mechanisms of CTLA4 and CTLA4-Ig therapies