There are three key areas of research currently ongoing in the lab:
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 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 will explore the hypothesis that the family of FAM83 proteins are key regulators of CK1, which act by directing CK1 isoforms to distinct subcellular compartments and substrates. We will dissect the role of PAWS1 and other FAM83 family members in CK1 biology and human disease and potentially uncover therapeutic opportunities. Two key research objectives are:
1. Understanding how FAM83G/PAWS1 regulates CK1α in Wnt and BMP signalling and disease.
2. Delineate the molecular mechanisms by which different FAM83 proteins target specific CK1 isoforms to specific subcellular compartments and substrates in response to different signalling cues.
B: Refining Affinity-directed PROtein Missile (AdPROM) System and expanding its applications in research and therapeutics. 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 AdPROM system to target endogenous proteins for efficient degradation. We aim to develop this system further to engineer highly efficient inducible AdPROM. 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.
C. Understand how TGF-beta/BMP signalling is regulated in different biological and disease contexts. TGFβ/BMP signalling pathways play fundamental roles during embryogenesis and in tissue homeostasis and aberrant signalling is associated with many human diseases including fibrosis, bone/immune disorders, cancer and metastasis. Past research from our lab has identified the regulation of TGF-beta/BMP pathways by reversible phosphorylation and ubiquitylation processes. The current research focusses on utilising cutting-edge genome-editing tools to understand the context-specific regulation of the TGF-beta and BMP signalling pathways in order to uncover effective therapeutic targets and strategies.
Please contact us for latest opportunities to undertake these projects in the lab.