On June 14, 2019, EMBO Journal published a research article entitled “PTPN3 acts as a tumor suppressor and boosts TGF-β signaling independent of its phosphatase activity” by Xin-Hua Feng Lab and collaborative laboratories.
TGF-β controls a variety of cellular functions. Dysregulation of TGF-β is commonly found in human diseases such as cancer. Since the tight control of TGF- signaling is particular important in maintaining the normal function of cell and tissue homeostasis, it is significant to identify additional key players in regulating TGF- signaling pathway. The authors found that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates TGF- signaling independent of its phosphatase activity. PTPN3 stabilizes TGF- type I receptor (TRI) through attenuating the interaction between TβRI with the Smad7-Smurf2 E3 ligase. Consequently, PTPN3 facilitates TGF--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- signaling and abolishes its tumor suppressive function. These findings add PTPN3 as a novel regulator of TGF- signaling and elucidate an essential function of PTPN3 in regulating tumor progression. Understanding how cancer-derived mutants of PTPN3 function in tumorigenesis has important clinical implications in cancers and other diseases.
Cartoon: A working model for the role of PTPN3 on TGF-β signaling
Links: http://m.emboj.embopress.org/content/early/2019/06/13/embj.201899945
