FAF1 phosphorylation by AKT accumulates TGF-β type II receptor and drives breast cancer metastasis

TGF-beta is pro-metastatic for the late-stage breast cancer cells. Despite recent progress, the regulation of TGF-beta type II receptor remains uncertain. Here we report that FAF1 destabilizes T beta RII on the cell surface by recruiting the VCP/E3 ligase complex, thereby limiting excessive TGF-beta response. Importantly, activated AKT directly phosphorylates FAF1 at Ser 582, which disrupts the FAF1-VCP complex and reduces FAF1 at the plasma membrane. The latter results in an increase in TbRII at the cell surface that promotes both TGF-beta-induced SMAD and non-SMAD signalling. We uncover a metastasis suppressing role for FAF1 through analyses of FAF1-knockout animals, various in vitro and in vivo models of epithelial-to-mesenchymal transition and metastasis, an MMTV-PyMT transgenic mouse model of mammary tumour progression and clinical breast cancer samples. These findings describe a previously uncharacterized mechanism by which TbRII is tightly controlled. Together, we reveal how SMAD and AKT pathways interact to confer pro-oncogenic responses to TGF-beta.