Ligands of the Transfroming Growth Factor-beta (TGF-beta) superfamily control numerous cellular processes such as proliferation, apoptosis, differentiation, adhesion and mobility. As a result, it is well established that they play an essential role in cancer. TGF-beta signalling has been implicated in both tumour suppression and progression. TGF-beta signals predominantly through receptor-regulated Smads (R-Smads), Smad2 and Smad3, but several lines of evidence from the Hill’s lab suggest that TGF-beta can also strongly induce phosphorylation and consequently signalling by Smad1 and Smad5 in epithelial cells. Moreover, our recent results have shown that Smad1/5 activation by TGF-beta is not required for its growth inhibitory effects, but rather is specifically required for TGF-beta-induced anchorage-independent growth, suggesting a relevant role of this novel mode of signalling in tumor progression. The first aim of this project is the accurate molecular description of TGF-beta-induced activation of Smad1/5. We will focus both on the receptor complexes responsible and the types of Smad complexes that result. Then, we will study which genes are induced by this novel mode of TGF-beta signalling. Finally, its functional relevance in normal epithelial cells and in tumorigenesis will be assessed. If we can show that this novel branch of TGF-beta signalling plays a role in tumour growth, then it could provide a good therapeutic target in cancer.