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Nat Commun. 2014 Jul 21;5:4451. doi: 10.1038/ncomms5451.

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

Author information

1
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
2
Ventana Medical Systems Inc, 1910 East Innovation Park Drive, Tucson, Arizona 85755, USA.
3
Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, La Jolla, California 92161, USA.

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.

PMID:
25043713
PMCID:
PMC4107319
DOI:
10.1038/ncomms5451
[Indexed for MEDLINE]
Free PMC Article

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