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.转化生长因子β（Transforming Growth Factor-β, TGF-β）在发育过程中调控多种细胞功能。异常的TGF-β应答常见于癌症等人类疾病中，这提示TGF-β信号通路必须受到严格调控。本研究发现，非受体型蛋白酪氨酸磷酸酶3（Protein Tyrosine Phosphatase Non-receptor 3, PTPN3）可在不依赖其磷酸酶活性的前提下，显著增强TGF-β信号通路。PTPN3通过削弱Smad泛素调节因子2（Smad Ubiquitination Regulatory Factor 2, Smurf2）与转化生长因子βⅠ型受体（Transforming Growth Factor-β type I receptor, TβRI）的相互作用，稳定TβRI的表达。由此，PTPN3可促进TGF-β诱导的受体调节型Smad（Receptor-regulated Smad, R-Smad）磷酸化、转录应答及后续的生理应答。尤为重要的是，PTPN3第232位氨基酸残基处的亮氨酸向精氨酸的替换（L232R）——这是肝内胆管癌（intrahepatic cholangiocarcinoma, ICC）中常见的突变类型——会使其丧失增强TGF-β信号通路的功能，并消除其肿瘤抑制作用。本研究揭示了PTPN3在正常生理及疾病进程中调控TGF-β信号通路的关键作用。