Reversible Human TGF-β Signal Shifting between Tumor Suppression and Fibro-Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions

Journal of Clinical Medicine
Katsunori YoshidaKazuichi Okazaki

Abstract

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (T...Continue Reading

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Citations

Jul 2, 2016·Journal of Clinical Medicine·Aristidis Moustakas, Carl-Henrik Heldin
Jul 18, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jinqiang ZhangTong Wu
May 15, 2020·Journal of Cellular and Molecular Medicine·Hanyan DingYan Yang
Sep 8, 2017·American Journal of Physiology. Renal Physiology·Taketsugu HamaHiroyuki Suzuki
May 29, 2018·Archives of Toxicology·Seddik HammadGianluigi Giannelli
Apr 9, 2020·Cells·Natascha RoehlenThomas F Baumert
Jul 15, 2017·World Journal of Gastroenterology : WJG·Erika Hernández-AquinoPablo Muriel
Apr 10, 2019·International Journal of Molecular Sciences·Jacopo BaglieriTatiana Kisseleva
Apr 25, 2018·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Andrea ManciniClaudio Festuccia
Oct 20, 2018·Hepatology Research : the Official Journal of the Japan Society of Hepatology·Erika Ramos-TovarPablo Muriel
May 2, 2018·World Journal of Gastroenterology : WJG·Erika Hernández-Aquino, Pablo Muriel
Dec 20, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Cheng-Yi HuangChun-Lin Chen
Dec 29, 2020·Phytotherapy Research : PTR·Venkatasubramanian AishwaryaVenkatabalasubramanian Sivaramakrishnan
Mar 30, 2021·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Xiangpeng HuJun Liu

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