PTPN3 acts as a tumor suppressor and boosts TGF-β signaling independent of its phosphatase activity

TGF-β controls a variety of cellular functions during development. Abnormal TGF-β responses are commonly found in human diseases such as cancer, suggesting that TGF-β signaling must be tightly regulated. Here, we report that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates...

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Published in:The EMBO journal 2019-07, Vol.38 (14), p.e99945
Main Authors: Yuan, Bo, Liu, Jinquan, Cao, Jin, Yu, Yi, Zhang, Hanchenxi, Wang, Fei, Zhu, Yezhang, Xiao, Mu, Liu, Sisi, Ye, Youqiong, Ma, Le, Xu, Dewei, Xu, Ningyi, Li, Yi, Zhao, Bin, Xu, Pinglong, Jin, Jianping, Xu, Jianming, Chen, Xi, Shen, Li, Lin, Xia, Feng, Xin-Hua
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Hep G2 Cells
Humans
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Mice
Neoplasm Transplantation
Phosphorylation
Protein Stability
Protein Tyrosine Phosphatase, Non-Receptor Type 3 - genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 3 - metabolism
Receptor, Transforming Growth Factor-beta Type I - chemistry
Receptor, Transforming Growth Factor-beta Type I - metabolism
Signal Transduction
Smad Proteins - metabolism
Transforming Growth Factor beta - metabolism
Ubiquitin-Protein Ligases - metabolism
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Summary:TGF-β controls a variety of cellular functions during development. Abnormal TGF-β responses are commonly found in human diseases such as cancer, suggesting that TGF-β signaling must be tightly regulated. Here, we report that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates TGF-β signaling independent of its phosphatase activity. PTPN3 stabilizes TGF-β type I receptor (TβRI) through attenuating the interaction between Smurf2 and TβRI. Consequently, PTPN3 facilitates TGF-β-induced R-Smad phosphorylation, transcriptional responses, and subsequent physiological responses. Importantly, the leucine-to-arginine substitution at amino acid residue 232 (L232R) of PTPN3, a frequent mutation found in intrahepatic cholangiocarcinoma (ICC), disables its role in enhancing TGF-β signaling and abolishes its tumor-suppressive function. Our findings have revealed a vital role of PTPN3 in regulating TGF-β signaling during normal physiology and pathogenesis.
ISSN:0261-4189
1460-2075
DOI:10.15252/embj.201899945