title: GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Lopez-Sanchez
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dunkel
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Yoon-Seok
authors.initials: YS
authors.lastname: Roh
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Yash
authors.initials: Y
authors.lastname: Mittal
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.affiliation: Ventana Medical Systems Inc, 1910 East Innovation Park Drive, Tucson, Arizona 85755, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Muranyi
authors.affiliation: Ventana Medical Systems Inc, 1910 East Innovation Park Drive, Tucson, Arizona 85755, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Singh
authors.affiliation: Ventana Medical Systems Inc, 1910 East Innovation Park Drive, Tucson, Arizona 85755, USA.
authors.forename: Kandavel
authors.initials: K
authors.lastname: Shanmugam
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Nakon
authors.initials: N
authors.lastname: Aroonsakool
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.affiliation: Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, La Jolla, California 92161, USA.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Ho
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D003094:Collagen; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020797:Receptor, Platelet-Derived Growth Factor beta; D016212:Transforming Growth Factor beta; D033921:Vesicular Transport Proteins; C502451:CCDC88A protein, human; C527550:Ccdc88a protein, mouse