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.


Selected publications from Dr Nadia Kershaw

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

Lab research projects

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