Overview
Tribbles (TRIB) pseudokinases are non-catalytic proteins that control phosphorylation and ubiquitin signalling-outputs in cells. Due to the diverse biological functions of TRIB2, its disregulation is a factor in multiple human diseases, including cancer.
About this opportunity
We recently discovered that human TRIB2 mutations result in a disorder that we have termed ‘TRIB2 syndrome’, characterized by microcephaly in children. Modelling demonstrates that disease-associated mutations alter TRIB2 proteostasis. Excitingly, TRIB2 has the propensity to form insoluble amyloid-like structures in vitro. During the PhD, biophysical and cellular workflows will be employed to discover how loss of functional TRIB2 causes TRIB2 syndrome, and to examine if small molecules developed by the iCASE partner Sulantrix modulate TRIB2 proteostasis/aggregation.
The 3.5 year PhD research project provides intensive training in cell signalling, biochemistry, molecular biology (Liverpool), structural biology (Leeds) and small molecule screening (Sulantrix, Liverpool) techniques.
PhD Objectives:
- Characterize TRIB2 syndrome in human cell models, analysing the relevance of aggrephagy/macroautophagy systems
- Structural biology (cryo-EM) to study mechanisms of TRIB2 proteostasis/aggregation.
- With https://sulantrix.com/, perform small molecule screens to identify compounds that modulate TRIB2 signalling.
The studentship includes a placement at Sulantrix, including training not typically available in academic labs, such as high-throughput liquid handling and small molecule screening. This would suit students looking for training exposure in both academia and industrial environments. All supervisors are committed to open, supportive communication and will meet regularly with the student during the phases of the training journey between Liverpool and Leeds. All supervisors are committed to EDI policies and student mental health support. We actively encourage students to maintain flexible work-life balances, re-enforcing that a PhD studentship is a training experience that permits skills (both scientific and transferable) to be gained as relevant to future careers in and outside of academia.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
iCASE industrial partner web link: https://sulantrix.com/
Further reading
1. Rigby E et al (2026) Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukaemia. BiorXiv doi: 10.1101/2025.10.03.680259v1
2. Harris JA, et al (2022) Analysis of human Tribbles 2 pseudokinase. Methods In Enzymology 667 (Academic Press) doi: 10.1016/bs.mie.2022.03.025
3. Shrestha S et al (2020) Cataloguing the dead: breathing new life into pseudokinase research. The FEBS Journal. 287:4150. doi: doi/10.1111/febs.15246
4. Walden M et al (2019) Metabolic control of SHMT2 oligomerization regulates ubiquitin-dependent inflammatory cytokine signaling. Nature doi: 10.1038/s41586-019-1232-1
5. Foulkes DM et al (2018) Covalent inhibitors of EGFR family protein kinase inhibitors induce degradation of human TRIB2 in cancer cells. Science Signaling doi: 10.1126/scisignal.aat7951
6. Eyers PA et al (2017). Tribbles in the 21st century: The Evolving roles of Tribbles pseudokinases in Biology and Disease. Trends In Cell Biology doi: 10.1016/j.tcb.2016.11.002