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Protein Tyrosine Phosphatase Non-receptor 3 Acts as a Tumor Suppressor and Boosts TGF-b Signaling Independent of its Phosphatase Activity

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE127903 | GEO | 2019/03/27

REPOSITORIES: GEO

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Project description:This model is from the article: Dynamics and feedback loops in the transforming growth factor β signaling pathway. Wegner K, Bachmann A, Schad JU, Lucarelli P, Sahle S, Nickel P, Meyer C, Klingmüller U, Dooley S, Kummer U. Biophys Chem. 2012 Jan 5. 22284904 , Abstract: Transforming growth factor β (TGF-β) ligands activate a signaling cascade with multiple cell context dependent outcomes. Disruption or disturbance leads to variant clinical disorders. To develop strategies for disease intervention, delineation of the pathway in further detail is required. Current theoretical models of this pathway describe production and degradation of signal mediating proteins and signal transduction from the cell surface into the nucleus, whereas feedback loops have not exhaustively been included. In this study we present a mathematical model to determine the relevance of feedback regulators (Arkadia, Smad7, Smurf1, Smurf2, SnoN and Ski) on TGF-β target gene expression and the potential to initiate stable oscillations within a realistic parameter space. We employed massive sampling of the parameters space to pinpoint crucial players for potential oscillations as well as transcriptional product levels. We identified Smad7 and Smurf2 with the highest impact on the dynamics. Based on these findings, we conducted preliminary time course experiments. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Protein Tyrosine Phosphatase Non-receptor 3 Acts as a Tumor Suppressor and Boosts TGF-b Signaling Independent of its Phosphatase Activity

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