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

ABSTRACT: TGF-? is pro-metastatic for the late-stage breast cancer cells. Despite recent progress, the regulation of TGF-? type II receptor remains uncertain. Here we report that FAF1 destabilizes T?RII on the cell surface by recruiting the VCP/E3 ligase complex, thereby limiting excessive TGF-? 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 T?RII at the cell surface that promotes both TGF-?-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 T?RII is tightly controlled. Together, we reveal how SMAD and AKT pathways interact to confer pro-oncogenic responses to TGF-?.

SUBMITTER: Xie F

PROVIDER: S-EPMC5414047 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Xie Feng F Jin Ke K Shao Li L Fan Yao Y Tu Yifei Y Li Yihao Y Yang Bin B van Dam Hans H Ten Dijke Peter P Weng Honglei H Dooley Steven S Wang Shuai S Jia Junling J Jin Jin J Zhou Fangfang F Zhang Long L

Nature communications 20170426

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 sur ...[more]

PMID: 28443643

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Project description:BackgroundMore than 90% of the mortality of triple-negative breast cancer (TNBC) patients is attributed to cancer metastasis with organotropism. The lung is a frequent site of TNBC metastasis. However, the precise molecular mechanism for lung-specific metastasis of TNBC is not well understood.MethodsRNA sequencing was performed to identify patterns of gene expression associated with lung metastatic behavior using 4T1-LM3, MBA-MB-231-LM3, and their parental cells (4T1-P, MBA-MB-231-P). Expressions of RGCC, called regulator of cell cycle or response gene to complement 32 protein, were detected in TNBC cells and tissues by qRT-PCR, western blotting, and immunohistochemistry. Kinase activity assay was performed to evaluate PLK1 kinase activity. The amount of phosphorylated AMP-activated protein kinase α2 (AMPKα2) was detected by immunoblotting. RGCC-mediated metabolism was determined by UHPLC system. Oxidative phosphorylation was evaluated by JC-1 staining and oxygen consumption rate (OCR) assay. Fatty acid oxidation assay was conducted to measure the status of RGCC-mediated fatty acid oxidation. NADPH and ROS levels were detected by well-established assays. The chemical sensitivity of cells was evaluated by CCK8 assay.ResultsRGCC is aberrantly upregulated in pulmonary metastatic cells. High level of RGCC is significantly related with lung metastasis in comparison with other organ metastases. RGCC can effectively promote kinase activity of PLK1, and the activated PLK1 phosphorylates AMPKα2 to facilitate TNBC lung metastasis. Mechanistically, the RGCC/PLK1/AMPKα2 signal axis increases oxidative phosphorylation of mitochondria to generate more energy, and promotes fatty acid oxidation to produce abundant NADPH. These metabolic changes contribute to sustaining redox homeostasis and preventing excessive accumulation of potentially detrimental ROS in metastatic tumor cells, thereby supporting TNBC cell survival and colonization during metastases. Importantly, targeting RGCC in combination with paclitaxel/carboplatin effectively suppresses pulmonary TNBC lung metastasis in a mouse model.ConclusionsRGCC overexpression is significantly associated with lung-specific metastasis of TNBC. RGCC activates AMPKα2 and downstream signaling through RGCC-driven PLK1 activity to facilitate TNBC lung metastasis. The study provides implications for RGCC-driven OXPHOS and fatty acid oxidation as important therapeutic targets for TNBC treatment.

Dataset Information

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

Publications

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

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