PTPN3 Acts as a Tumor Suppressor and Boosts TGF-? Signaling Independent of its Phosphatase Activity

TGF-? controls a variety of cellular functions during development. Abnormal TGF-? responses are commonly found in human diseases such as cancer, suggesting that TGF-? signaling must be tightly regulated. Here we report that Protein Tyrosine Phosphatase Non-receptor 3 (PTPN3) profoundly potentiates TGF-? signaling independent of its phosphatase activity. PTPN3 stabilizes TGF-? type I receptor (T?RI) through attenuating the interaction between Smurf2 and T?RI. 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), disable its role in enhancing TGF-? signaling and abolishes its tumor suppressive function. Our findings have revealed a vital role of PTPN3 in regulating TGF-? signaling during normal physiology and pathogenesis.