Mechanistic Insights into Deregulated TGF-β Family Signalling in Human Disease.

Deregulation of TGF-β family signalling underlies some serious human diseases, including cancer, the Marfan syndromes, and other connective tissue disorders. Recent work in my lab has focused on working out how mutations in key components of TGF-β family signalling pathways cause these diseases. Shprintzen-Goldberg syndrome (SGS) is a Marfan-related syndrome caused by heterozygous point mutations in the co-repressor SKI, which is a negative regulator of TGF-β signalling that is rapidly degraded upon TGF-β or Activin stimulation. The molecular consequences of these mutations, however, have not been well understood. Using a combination of structural biology, genome editing and biochemistry we have shown that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3, which are the downstream signal transducers of the TGF-β and Activin signalling pathways. This results in stabilization of SKI and consequently attenuation of TGF-β responses, in both knockin cells expressing an SGS mutation, and in fibroblasts from SGS patients. Thus, we conclude that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, which has important implications for other Marfan-related syndromes. Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF-β family type I receptor. ACVR1R206H is a frequent mutation found in patients with these diseases. The relevant ligand required to activate this mutant receptor is thought to be Activin A. To obtain insights into the underlying molecular mechanism we have used a combination of biochemistry, optogenetics and live imaging in both knockin cells and in cells from DIPG patients. Our results demonstrate that in contrast to wild type TGF-β family receptors, ACVR1R206H activation does not require any upstream kinases. Instead we show that it is predominantly activated via Activin A-dependent receptor clustering, which induces its auto-activation, leading to downstream SMAD1/5 phosphorylation. The relevance of this for the pathogenesis of FOP and DIPG will be discussed.