Understanding mechanisms of reversible phosphorylation and ubiquitylation in cell signalling and disease.
Reversible phosphorylation and ubiquitylation of proteins underpin the regulation of many cell signalling processes. Faulty signalling cascades account for many human diseases, including skin and bone disorders, cancer and neurodegenerative diseases.
Our group focusses on two key areas of research:
A: FAM83 family as key regulators CK1 isoforms: The CK1 family of constitutively active protein kinases controls a plethora of cellular processes and their misregulation is associated with many human diseases, yet the regulation of CK1 activity, substrate specificity, subcellular localisation and turnover are still understood poorly. Building on our recent discoveries, the research in our group is exploring the hypothesis that the family of FAM83 proteins are key regulators of CK1 isoforms, which act by directing specific CK1 isoforms to distinct subcellular compartments and substrates. We have shown that FAM83G (aka PAWS1) mediates Wnt signalling through association with CK1α. Moreover, pathogenic PAWS1 mutations that cause palmoplantar hyperkeratosis are unable to interact with CK1α, and consequently fail to mediate Wnt signalling. We have also shown that FAM83D directs CK1α to the mitotic spindle to ensure proper spindle positioning and timely cell division.
We aim to continue to dissect the roles of FAM83 proteins in CK1 biology and human diseases. Some key research objectives are:
- Understand the molecular basis of FAM83-CK1 interaction.
- Identify, and characterise the roles of, PAWS1-dependent CK1α substrates in Wnt signalling and FAM83D-dependent CK1α substrates in mitosis.
- Delineate the molecular mechanisms by which other FAM83 proteins direct specific CK1 isoforms to specific subcellular compartments and substrates in response to different signalling cues.
B: Harnessing the ubiquitin proteasome system for drug discovery: Efficient targeted proteolysis of endogenous proteins is desirable in therapeutics and as a research toolkit. Gene knockouts are irreversible and, for many proteins, not feasible. Similarly, RNA interference approaches necessitate prolonged treatments, can lead to incomplete knockdowns and are often associated with off-target effects. Direct proteolysis of target proteins can overcome these limitations. Our lab has developed the Affinity-directed PROtein Missile (AdPROM) System to target endogenous proteins for efficient degradation. We aim to develop this system further to engineer highly efficient inducible AdPROM as well as adapt it to rapidly establish the best E3 ligases for most efficient degradation of target proteins. We want to exploit AdPROM to rapidly test the druggability of so-called “undruggable” targets by proteolysis. We will also explore the therapeutic potential of AdPROM in clearing misfolded proteins that are hallmarks of many neurodegenerative diseases.