The Developmental Signalling Laboratory headed by Caroline Hill focuses on cell signalling in early vertebrate development and disease. Our work seeks to understand how TGF-b family signalling pathways function normally in early vertebrate development and in adult untransformed cells, and how these signalling pathways are perturbed in disease, in particular in cancer and the Marfan-related syndromes.
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We are looking for a highly motivated postdoc with proven research abilities and
excellent publication record to work on structural projects using Cryo-EM and crystallography to gain mechanistic insights into TGF-β family signalling in health and disease.
We have recently been studying the effects of mutations in the transcriptional repressor SKI that occur in the Marfan-related disorder, Shprintzen-Goldberg syndrome. SKI normally binds with SMAD4 (one of the SMADs that acts downstream of TGF-β family ligands) to TGF-β and activin response elements in the absence of signalling to repress transcription. It is then rapidly degraded upon TGF-β/activin signalling as a result of forming a complex with activated SMADs (induced downstream of TGF-β/activin) and the E3 ubiquitin ligase RNF111 (also called Arkadia). This frees up the TGF-β/activin response elements for activated SMAD complexes to bind to drive transcription. We have shown that SKI containing the point mutations that occur in Shprintzen-Goldberg syndrome is not degraded and in this context, TGF-β/activin transcriptional responses are inhibited.
We have very recently solved the structure of a complex comprising SKI–phosphorylated SMAD2–SMAD4, that sheds light on the effect of the SKI mutations on SKI–SMAD binding. One of the main ambitions of this new project is to understand now using structural, biochemical and biophysical approaches, how this complex is recognised by RNF111 for proteosomal degradation. We also want to understand how the full length activated SMAD complexes bind at the TGF-β/activin-responsive elements with cooperating transcription factors to activate transcription. We are investigating this for wild type SMADs, but also in the context of another disease, Myhre syndrome, where SMAD4 contains an activating mutation.
Postdoctoral Fellows at the Crick lead their own projects, contribute to other projects on a collaborative basis (both in the lab and with external collaborators) and may guide PhD students in their research. The ability to work in a team is essential.
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