GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis

Inmaculada Lopez-Sanchez, Ying Dunkel, Yoon-Seok Roh, Yash Mittal, Samuele De Minicis, Andrea Muranyi, Shalini Singh, Kandavel Shanmugam, Nakon Aroonsakool, Fiona Murray, Samuel B. Ho, Ekihiro Seki, David A. Brenner and Pradipta Ghosh ()
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Inmaculada Lopez-Sanchez: University of California, San Diego
Ying Dunkel: University of California, San Diego
Yoon-Seok Roh: University of California, San Diego
Yash Mittal: University of California, San Diego
Samuele De Minicis: University of California, San Diego
Andrea Muranyi: Ventana Medical Systems Inc, 1910 East Innovation Park Drive
Shalini Singh: Ventana Medical Systems Inc, 1910 East Innovation Park Drive
Kandavel Shanmugam: Ventana Medical Systems Inc, 1910 East Innovation Park Drive
Nakon Aroonsakool: University of California, San Diego
Fiona Murray: University of California, San Diego
Samuel B. Ho: Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego
Ekihiro Seki: University of California, San Diego
David A. Brenner: University of California, San Diego
Pradipta Ghosh: University of California, San Diego

Nature Communications, 2014, vol. 5, issue 1, 1-18

Abstract: Abstract Progressive liver fibrosis is characterized by the deposition of collagen by activated hepatic stellate cells (HSCs). Activation of HSCs is a multiple receptor-driven process in which profibrotic signals are enhanced and antifibrotic pathways are suppressed. Here we report the discovery of a signalling platform comprising G protein subunit, Gαi and GIV, its guanine exchange factor (GEF), which serves as a central hub within the fibrogenic signalling network initiated by diverse classes of receptors. GIV is expressed in the liver after fibrogenic injury and is required for HSC activation. Once expressed, GIV enhances the profibrotic (PI3K-Akt-FoxO1 and TGFβ-SMAD) and inhibits the antifibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favour of fibrosis, all via activation of Gαi. We also provide evidence that GIV may serve as a biomarker for progression of fibrosis after liver injury and a therapeutic target for arresting and/or reversing HSC activation during liver fibrosis.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5451

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DOI: 10.1038/ncomms5451

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