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

TGF-β is pro-metastatic for the late-stage breast cancer cells. Despite recent progress, the regulation of TGF-β type II receptor remains uncertain. Here we report that FAF1 destabilizes TβRII on the cell surface by recruiting the VCP/E3 ligase complex, thereby limiting excessive TGF-β 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 TβRII at the cell surface that promotes both TGF-β-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 TβRII is tightly controlled. Together, we reveal how SMAD and AKT pathways interact to confer pro-oncogenic responses to TGF-β.
Mesh Terms:
A549 Cells, Adaptor Proteins, Signal Transducing, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Female, HEK293 Cells, HeLa Cells, Humans, MCF-7 Cells, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Neoplasm Metastasis, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Transplantation, Heterologous
Nat Commun
Date: Dec. 26, 2016
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