Functional And Mechanistic Studies Of PTPN3 In TGF-β Signaling Pathway

As an extremely essential cytokine,Transforming Growth Factor β(TGF-β)controls a variety of cellular functions including cell proliferation,differentiation,apoptosis and embryonic development.On the cell surface,the ligand binds to the type Ⅱ receptor(TβRII),which recruits and phosphorylates the type Ⅰ receptor(TβRI).In canonical TGF-β signaling,the activated TβRI phosphorylates receptor-activated Smad(R-Smad,i.e.Smad2/3).Then phosphorylated R-Smad form a complex with common Smad(Co-Smad,i.e.Smad4)and become accumulated in the nucleus.Inside the nucleus,the Smad complex recruits transcription co-activators and regulates gene transcription in a context-dependent manner.Dysregulation of TGF-(3 is commonly found in human diseases such as immune diseases,fibrosis,cardiovascular disease,abnormal embryonic development and cancer,suggesting that TGF-P signaling is normally under tight control.TGF-βsignaling plays dual roles in the regulation of tumor progression.In the premalignant state,TGF-β has tumor-suppressive effects through accelerating growth inhibitory and apoptosis.However,TGF-(3 enhances metastasis,immune evasion and angiogenesis at later stages of tumor progression.Since the tight control of TGF-β signaling is particular important in maintaining the normal function of cell and tissue homeostasis,we have sought to identify additional key players in regulating TGF-β signaling pathway.PTPN3 belongs to the non-transmembrane protein tyrosine phosphatase(PTP)family.Accumulating evidence suggests that PTPN3 plays a critical role in the progression of a variety of human cancers,such as breast cancer,lung cancer,colon cancer and liver cancer.Despite its essential regulatory role in cancer,the mechanisms underlying how PTPN3 affects the tumor progression especially in liver cancer remain elusive.Here we report that PTPN3 stabilized TβRI through attenuating the interaction between Smurf2 and TβRI.Consequently,PTPN3 facilitated TGF-β-induced R-Smad phosphorylation,transcriptional responses and subsequent physiological responses.To our surprise,PTPN3 potentiated canonical TGF-β signaling independent of its phosphatase activity.Interestingly,the leucine-to-arginine substitution at amino acid residue 232(L232R)of PTPN3,a highly frequent mutation found in Intrahepatic Cholangiocarcinoma(ICC),completely lost its tumor suppressive function due to its failure to enhance TGF-βsignaling.Highlights:1.Our study reveals a vital role of PTPN3 as a new regulator in regulating TGF-βsignaling during normal physiology and pathogenesis.2.Our study adds a new function of PTPN3 independent of its phosphatase activity.3.Our study elucidates the tumor-suppressive mechanism of PTPN3 in liver cancer.4.Our study provides a new theoretical and experimental basis for the potential prevention and treatment of liver cancer.