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

Feng Xie, Ke Jin, Li Shao, Yao Fan, Yifei Tu, Yihao Li, Bin Yang, Hans van Dam, Peter ten Dijke, Honglei Weng, Steven Dooley, Shuai Wang, Junling Jia, Jin Jin, Fangfang Zhou () and Long Zhang ()
Additional contact information
Feng Xie: Life Sciences Institute and Innovation Center for Cell Signalling Network
Ke Jin: Life Sciences Institute and Innovation Center for Cell Signalling Network
Li Shao: State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease
Yao Fan: Life Sciences Institute and Innovation Center for Cell Signalling Network
Yifei Tu: Life Sciences Institute and Innovation Center for Cell Signalling Network
Yihao Li: Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600 2300 RC Leiden, The Netherlands
Bin Yang: University of California San Francisco
Hans van Dam: Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600 2300 RC Leiden, The Netherlands
Peter ten Dijke: Cancer Genomics Centre Netherlands, Leiden University Medical Center, Postbus 9600 2300 RC Leiden, The Netherlands
Honglei Weng: Medical Faculty Mannheim, Heidelberg University
Steven Dooley: Medical Faculty Mannheim, Heidelberg University
Shuai Wang: Institutes of Biology and Medical Science, Soochow University
Junling Jia: Life Sciences Institute and Innovation Center for Cell Signalling Network
Jin Jin: Life Sciences Institute and Innovation Center for Cell Signalling Network
Fangfang Zhou: Institutes of Biology and Medical Science, Soochow University
Long Zhang: Life Sciences Institute and Innovation Center for Cell Signalling Network

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15021

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