Podcast: Understanding growth signals

Secreted growth hormones and cytokines regulate the key physiological processes of growth and differentiation, as well as responses to injury and infection. My group is interested in how these signals are regulated inside the cell by phosphorylation and ubiquitination, how these pathways are perturbed in disease and how we may intervene to develop new drug treatments for patients. We address these problems using a multidisciplinary approach combining structural biology, cell biology and chemical biology. A major interest has been the BMP/TGF-beta family receptor serine/threonine kinase ACVR1/ALK2 which recruits and phosphorylates SMAD1/5/8 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 solved the crystal structure of ALK2 to define the effects of mutation and have identified a number of small molecule inhibitors that block the aberrant ALK2 signalling found in disease models. We are currently conducting a phase 2 clinical trial of the ALK2 inhibitor saracatinib for FOP patients in collaboration with clinicians in the UK, The Netherlands and Germany.

Phosphorylation can also form a control switch for protein substrates to be recruited to E3 ubiquitin ligases for degradation. We aim to define the substrate recognition motifs that enable E3 recruitment and to determine the 3D structures of E3 ligases to characterize their binding to substrates, regulatory partners and chemical inhibitors. We have focused especially on multi-subunit Cullin-RING E3 ligase complexes and have determined how BTB-Kelch E3 ligases assemble into Cullin3 complexes through their 3-box motif and how different substrate recognition domains assemble with the SOCS box motif to form Cullin5-dependent E3 ligases. 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, drug resistance 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.