Growth Factor Signalling and Ubiquitination

Our work is particularly focussed on the cross talk that regulates protein phosphorylation and ubiquitination. We aim to understand the molecular structure and function of protein kinases and E3 ligases and to characterize their binding to substrates, regulatory partners and chemical inhibitors. This work involves a multidisciplinary approach using structural, chemical and cell biology, as well as many collaborative studies with colleagues across industry and academia.

A major interest has been the BMP/TGF-beta family receptor serine/threonine kinase ACVR1/ALK2 which recruits and phosphorylates SMAD family transcription factors for the control of embryogenesis, stem cell differentiation and iron metabolism. Mutations in this receptor drive the childhood brain tumour diffuse intrinsic pontine glioma, as well as the musculoskeletal disorder fibrodysplasia ossificans progressiva (FOP). We have elucidated the structural basis of disease-causing mutations and identified a number of small molecule inhibitors that block the aberrant ALK2 signalling found in disease models. We have taken this work into the clinic with an ongoing phase 2 clinical trial "STOPFOP" that is exploring saracatinib as an ALK2 kinase inhibitor for the treatment of FOP in collaboration with clinicians in the UK, The Netherlands, Germany, and the US.

Our work has also revealed a novel mechanism of tumorigenesis through E3 ligase neofunction. We discovered that mutations in the E3 ligase KBTBD4 change its substrate specificity resulting in the KBTBD4-dependent degradation of the CoREST/LSD1/HDAC complex and epigenetic reprogramming in medulloblastoma. This work identifies KBTBD4 as a new druggable target for tumour-specific therapies. E3 ligases are also attractive targets for the design of small molecule PROTACs, which are bivalent chemical binders that recruit neo-substrates to an E3 ligase for targeted protein degradation. This approach has potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, and modulating 'undruggable' targets. We aim to develop small molecule binders for novel E3 ligases to expand the repertoire of E3s suitable for PROTAC development to maximise the potential of this technology.