Hill lab

Developmental Signalling Laboratory

: A new branch of TGF-β signalling through Smad1/5

An image montage showing three different kinds of signalling in zebrafish embryos and a breast cancer organoid.

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Several years ago we made the unexpected discovery that TGF-β induces phosphorylation of Smad1/5 in the majority of epithelial cells, cancer cell lines and fibroblasts that we have tested, in addition to inducing Smad2/3 phosphorylation.

We want to establish the function of this branch of TGF-β/Smad signalling and determine its importance in tumour development and dissemination.

We have shown that this pathway results in the formation of phosphorylated Smad1/5-Smad4 complexes as well as complexes between phosphorylated Smad1/5 and phosphorylated Smad2/3. We have shown that TGF-β-induced SMAD1/5 phosphorylation requires members of two classes of type I receptor, TGFBR1 and ACVR1, and we have established a new paradigm for receptor activation where TGFBR1 phosphorylates and activates ACVR1, which phosphorylates SMAD1/5.

Using ChIP-seq we have identifed the genomic binding sites of the Smad1/5-Smad4 complexes in response to TGF-β which has led us to identify the target genes activated. We have gone on to show that epithelial-to-mesenchymal transition requires this branch of TGF-β signalling (Ramachandran et al., 2018 Elife 7:e31756)

We are now using CRISPR-Cas9 technology to knockout this pathway in cancer cells, and in a mouse model of breast cancer to elucidate the importance of this branch of TGF-β signalling in cancer.