Lab Focus: Structural Biology of Cytokine Signalling

Cytokines are small protein messengers that transmit information from the outside of the cell to the inside of the cell. They are important regulators of the immune system, and when these messangers misfire, it can result in inflammatory disease, autoimmunity or cancer. Our research is focused on determining what these molecules look like, how they function, and how the signals they send are regulated.

We generate detailed 3D “pictures” of these molecules, and the molecules they interact with. We use this information to understand how they work, what is going wrong in a disease setting, and to try to design drugs to change how they function.

Research Interest

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 signaling 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:

• 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.
• 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.
• 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.