Dr Nadia Kershaw, Lab Head | WEHI Researcher Profile

Q: Structure and function of the Thrombopoietin Receptor

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. Impared signalling causes low-platelet counts. The architecture of TpoR is distinct from any other cytokine receptor and there is a complete lack of structural data for it. We are using crystallography and CryoEM to study the Thrombopoietin Receptor and its interactions with clinically used agonists. 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).

Q: Structural and mechanistic studies on Suppressors of Cytokine Signaling.

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).

Q: Novel modulators of T-cell activity in autoimmunity and cancer

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

Q: Structure-function studies on the cytokine regulator LNK

The process of blood cell development is tightly controlled by regulatory proteins. When these regulatory systems go awry, too many and incorrect types of blood cells can be produced, resulting in blood cancers. LNK is a protein that acts like a brake on blood cell production, keeping cell growth in check. Patient data suggest that malfunctions in LNK, specifically mutations that disable it, might be a driving force behind some blood cancers. LNK performs its regulatory activities by regulating the JAK/STAT pathway, but exactly how it does this is poorly understood. This project will combine structural biology, protein chemistry, mass spectrometry and microscopy approaches to understand the function of LNK in healthy cells, and how/why patient mutations result in disease. We hope this will help us to determine whether LNK is an appropriate target for therapeutic interventimass spectrometry aon.

About

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:

1. We have a strong focus on understanding molecules that regulate JAK/STAT signaling such as the Suppressors of Cytokine Signalling (SOCS). Inhibition of some SOCS proteins could provide a possible mechanism for improving cancer immunotherapy.
2. We are studying the Thrombopoietin receptor, which is important in regulating blood development, and we are trying to develop new strategies for targeting the dysregulated Thrombopoietin signalling that can drive myeloproliferative disease.
3. We are developing completely new immuno-modulatory molecules to allow improved control of T cell activity, with potential impact in the treatment of autoimmunity and cancer.

Education

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Selected publications from Dr Nadia Kershaw

Sarson-Lawrence KTG, Hardy JM, Iaria J, Stockwell D, Behrens K, Saiyed T, Tan C, Jebeli L, Scott NE, Dite TA, Nicola NA, Leis AP, Babon JJ, Kershaw NJ. Cryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin. Nature Communications. 2024;15(1):10.1038/s41467-024-45356-2

Linossi EM, Li K, Veggiani G, Tan C, Dehkhoda F, Hockings C, Calleja DJ, Keating N, Feltham R, Brooks AJ, Li SS, Sidhu SS, Babon JJ, Kershaw NJ, Nicholson SE. Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nature Communications. 2021;12(1):10.1038/s41467-021-26983-5

Morris R, Zhang Y, Ellyard JI, Vinuesa CG, Murphy JM, Laktyushin A, Kershaw NJ, Babon JJ. Structural and functional analysis of target recognition by the lymphocyte adaptor protein LNK. Nature Communications. 2021;12(1):10.1038/s41467-021-26394-6

Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Science. 2018;27(12):10.1002/pro.3519

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. Nature Communications. 2018;9(1):10.1038/s41467-018-04013-1

Oxley EP, Kershaw NJ, Louis C, Goodall KJ, Garwood MM, Jee Ho SM, Voo VTF, Park H-Y, Iaria J, Wong LLL, Lebenbaum AG, Wiranata S, Pang ES, Edwards ESJ, D’Silva DB, Hansen J, van Zelm MC, O’Keeffe M, Hogarth PM, Haynes NM, Huntington ND, Wicks IP, Dickins RA. Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity. Cell Reports. 2024;43(10):10.1016/j.celrep.2024.114834

Zhang Y, Morris R, Brown GJ, Lorenzo AMD, Meng X, Kershaw NJ, Kiridena P, Burgio G, Gross S, Cappello JY, Shen Q, Wang H, Turnbull C, Lea-Henry T, Stanley M, Yu Z, Ballard FD, Chuah A, Lee JC, Hatch A-M, Enders A, Masters SL, Headley AP, Trnka P, Mallon D, Fletcher JT, Walters GD, Šestan M, Jelušić M, Cook MC, Athanasopoulos V, Fulcher DA, Babon JJ, Vinuesa CG, Ellyard JI. Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity. Journal of Experimental Medicine. 2024;221(4):10.1084/jem.20221080

Linossi EM, Li K, Veggiani G, Tan C, Dehkhoda F, Hockings C, Calleja DJ, Keating N, Feltham R, Brooks AJ, Li SS, Sidhu SS, Babon JJ, Kershaw NJ, Nicholson SE. Author Correction: Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nature Communications. 2023;14(1):10.1038/s41467-023-42706-4

Sarson-Lawrence KTG, Hardy JM, Iaria J, Saiyed T, Leis AP, Babon JJ, Kershaw NJ. Structural studies of the thrombopoietin–thrombopoietin receptor signalling complex. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323086734

Liang S, Tran E, Du X, Dong J, Sudholz H, Chen H, Qu Z, Huntington ND, Babon JJ, Kershaw NJ, Zhang Z-Y, Baell JB, Wiede F, Tiganis T. A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. Nature Communications. 2023;14(1):10.1038/s41467-023-40170-8

Liang S, Tran E, Du X, Dong J, Sudholz H, Chen H, Qu Z, Huntington ND, Babon JJ, Kershaw NJ, Zhang Z-Y, Baell JB, Wiede F, Tiganis T. A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. 2023;4(06-30):10.1101/2023.06.16.545220

Morris R, Keating N, Tan C, Chen H, Laktyushin A, Saiyed T, Liau NPD, Nicola NA, Tiganis T, Kershaw NJ, Babon JJ. Structure guided studies of the interaction between PTP1B and JAK. Communications Biology. 2023;6(1):10.1038/s42003-023-05020-9

Low RRJ, Fung KY, Gao H, Preaudet A, Dagley LF, Yousef J, Lee B, Emery-Corbin SJ, Nguyen PM, Larsen RH, Kershaw NJ, Burgess AW, Gibbs P, Hollande F, Griffin MDW, Grimmond SM, Putoczki TL. Correction to: S100 family proteins are linked to organoid morphology and EMT in pancreatic cancer. Cell Death & Differentiation. 2023;30(5):10.1038/s41418-023-01151-y

Low RRJ, Fung KY, Gao H, Preaudet A, Dagley LF, Yousef J, Lee B, Emery-Corbin SJ, Nguyen PM, Larsen RH, Kershaw NJ, Burgess AW, Gibbs P, Hollande F, Griffin MDW, Grimmond SM, Putoczki TL. S100 family proteins are linked to organoid morphology and EMT in pancreatic cancer. Cell Death & Differentiation. 2023;30(5):10.1038/s41418-023-01126-z

Doggett K, Keating N, Dehkhoda F, Bidgood GM, Meza Guzman LG, Leong E, Kueh A, Nicola NA, Kershaw NJ, Babon JJ, Alexander WS, Nicholson SE. The SOCS1 KIR and SH2 domain are both required for suppression of cytokine signaling in vivo. Cytokine. 2023;165:10.1016/j.cyto.2023.156167

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Lab research projects

Structure and function of the Thrombopoietin Receptor

Structural and mechanistic studies on Suppressors of Cytokine Signaling.

Novel modulators of T-cell activity in autoimmunity and cancer

Structure-function studies on the cytokine regulator LNK

Student research projects

Targeting cytokine signaling in blood cancer and inflammation: a structural biology approach

Graduate Research Masters/Honours/Masters by Coursework/PhD

More information

Targeting cytokine signaling in blood cancer and inflammation: a structural biology approach

Graduate Research Masters/Honours/Masters by Coursework/PhD

More information

View all student research projects

Dr Nadia Kershaw

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