Protein phosphorylation and ubiquitylation pathways play a central role in human diseases such as Parkinson’s, cancer and hypertension. Mutations in protein kinases cause around 1% of all Parkinson’s disease, and many kinases and ubiquitylation enzymes are mutated in human cancer and hypertension.
Our group focuses on understanding the components of signalling pathways that are mutated in neurodegenerative movement disorders (LRRK2, Fbxo7, PINK1, Parkin, TTBK2), hyperstension (WNK1, WNK4, SPAK, OSR1, Cullin3 and KLHL3) and cancer (PDK1, Akt, SGK, mTOR, LKB1, ARK5/NUAK1 and AMPK). The aim of our research is to work out how these pathways are organised, how they recognise signals, how the signal moves down the pathway to elicit physiological responses and what goes wrong in human disease. We hope that our findings will enable researchers to play the engineer in devising new strategies to treat disease.
In collaboration with Matthias Mann, we recently identified the first physiological substrate for the Parkinson’s disease-associated LRRK2 protein kinase, by showing that LRRK2 directly phosphorylates a subset of the Rab GTPases, on a residue lying within the middle of the effector interacting-switch II domain. We also defined a novel pathway by which the SGK3 protein kinase is activated, and found that SGK3 isoforms contribute to the resistance of breast cancer cells to Akt and PI3-kinase inhibitors. In collaboration with Thimo Kurz, we demonstrated that the KLHL3:CUL2 ubiquitin E3 ligase complex is mutated in patients with Gordon’s hypertension syndrome.