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Fam20C‐mediated phosphorylation of osteopontin is critical for its secretion but dispensable for its action as a cytokine in the activation of hepatic stellate cells in liver fibrogenesis

DOI: 10.1096/fj.201900880R DOI Help

Authors: Elena Tibaldi (University of Padova) , Alessandra Brocca (University of Padova) , Antonietta Sticca (University of Padova) , Elisabetta Gola (University of Padova) , Marco Pizzi (University of Padova) , Luciana Bordin (University of Padova) , Mario Angelo Pagano (University of Padova) , Marco Mazzorana (Diamond Light Source) , Gabriella Donà (University of Padova) , Paola Violi (University Hospital of Verona) , Oriano Marin (University of Padova) , Antonella Romano (University of Padova) , Paolo Angeli (University of Padova, Padova) , Amedeo Carraro (University Hospital of Verona) , Anna Maria Brunati (University of Padova)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Faseb Journal , VOL 34 , PAGES 1122 - 1135

State: Published (Approved)
Published: November 2019

Abstract: Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and in cultured activated hepatic stellate cells (HSCs), we show that OPN, besides being overexpressed, is substantially phosphorylated by family with sequence similarity 20, member C (Fam20C), formerly known as Golgi casein kinase (G‐CK), which is exclusively resident in the Golgi apparatus. In both experimental models, Fam20C becomes overactive when associated with a 500‐kDa multiprotein complex, as compared with the negligible activity in livers of sham‐operated rats and in quiescent HSCs. Fam20C knockdown not only confirmed the role of Fam20C itself in OPN phosphorylation, but also revealed that phosphorylation was essential for OPN secretion. However, OPN acts as a fibrogenic factor independently of its phosphorylation state, as demonstrated by the increased expression of Collagen‐I by HSCs incubated with either a phosphorylated or nonphosphorylated form of recombinant OPN. Collectively, our results confirm that OPN promotes liver fibrosis and highlight Fam20C as a novel factor driving this process by favoring OPN secretion from HSCs, opening new avenues for deciphering yet unidentified mechanisms underlying liver fibrogenesis.

Journal Keywords: bile duct ligation; Golgi apparatus; hepatic stellate cells; osteopontin; phosphorylation

Subject Areas: Biology and Bio-materials, Chemistry


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Added On: 14/01/2020 10:40

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Life Sciences & Biotech Health & Wellbeing Non-Communicable Diseases Chemistry Biochemistry

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