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; Pradipta Ghosh

doi:10.1038/ncomms5451

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, Pradipta Ghosh^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

78 Citations (Scopus)

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.

Original language	English
Article number	4451
Number of pages	18
Journal	Nature Communications
Volume	5
Early online date	21 Jul 2014
DOIs	https://doi.org/10.1038/ncomms5451
Publication status	Published - 21 Jul 2014

Bibliographical note

We thank Marilyn Farquhar (UCSD) and Mikel Garcia-Marcos (Boston U) for their
helpful comments and critiques during the preparation of this manuscript, Katsumi Miyai (Pathology, UCSD) for generously giving us access to liver autopsy samples used in this work, Timo Meerloo for help with the preparation of semithin cryosections used to perform the immunofluorescence analysis and Robert Esteban (Ventana Inc.) for optimization of IHC staining of liver sections. This work was supported by NIH grants CA160911 and DK099226, CAMS (Burroughs Wellcome Fund) and CSDA (Doris Duke Charitable Foundation) Awards to P.G. I.L.-S. was supported by American Heart Association (AHA no. 14POST20050025); Y.M. was supported by the Sarah Rogers Fellowship (UCSD). D.A.B was supported by P42ES010337, S.B.H. by Veterans Affairs Research Service, E.S. by R01AA020172, R01DK085252 and P42ES010337, and F.M. by
NIH HL091061.

Keywords

Cell signalling
Liver fibrosis
Pathogenesis

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Fiona Murray
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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.",

keywords = "Cell signalling, Liver fibrosis, Pathogenesis",

author = "Inmaculada Lopez-Sanchez and Ying Dunkel and Yoon-Seok Roh and Yash Mittal and {De Minicis}, Samuele and Andrea Muranyi and Shalini Singh and Kandavel Shanmugam and Nakon Aroonsakool and Fiona Murray and Ho, {Samuel B} and Ekihiro Seki and Brenner, {David A} and Pradipta Ghosh",

note = "We thank Marilyn Farquhar (UCSD) and Mikel Garcia-Marcos (Boston U) for their helpful comments and critiques during the preparation of this manuscript, Katsumi Miyai (Pathology, UCSD) for generously giving us access to liver autopsy samples used in this work, Timo Meerloo for help with the preparation of semithin cryosections used to perform the immunofluorescence analysis and Robert Esteban (Ventana Inc.) for optimization of IHC staining of liver sections. This work was supported by NIH grants CA160911 and DK099226, CAMS (Burroughs Wellcome Fund) and CSDA (Doris Duke Charitable Foundation) Awards to P.G. I.L.-S. was supported by American Heart Association (AHA no. 14POST20050025); Y.M. was supported by the Sarah Rogers Fellowship (UCSD). D.A.B was supported by P42ES010337, S.B.H. by Veterans Affairs Research Service, E.S. by R01AA020172, R01DK085252 and P42ES010337, and F.M. by NIH HL091061.",

year = "2014",

month = jul,

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doi = "10.1038/ncomms5451",

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T1 - GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis

AU - Lopez-Sanchez, Inmaculada

AU - Dunkel, Ying

AU - Roh, Yoon-Seok

AU - Mittal, Yash

AU - De Minicis, Samuele

AU - Muranyi, Andrea

AU - Singh, Shalini

AU - Shanmugam, Kandavel

AU - Aroonsakool, Nakon

AU - Murray, Fiona

AU - Ho, Samuel B

AU - Seki, Ekihiro

AU - Brenner, David A

AU - Ghosh, Pradipta

N1 - We thank Marilyn Farquhar (UCSD) and Mikel Garcia-Marcos (Boston U) for their helpful comments and critiques during the preparation of this manuscript, Katsumi Miyai (Pathology, UCSD) for generously giving us access to liver autopsy samples used in this work, Timo Meerloo for help with the preparation of semithin cryosections used to perform the immunofluorescence analysis and Robert Esteban (Ventana Inc.) for optimization of IHC staining of liver sections. This work was supported by NIH grants CA160911 and DK099226, CAMS (Burroughs Wellcome Fund) and CSDA (Doris Duke Charitable Foundation) Awards to P.G. I.L.-S. was supported by American Heart Association (AHA no. 14POST20050025); Y.M. was supported by the Sarah Rogers Fellowship (UCSD). D.A.B was supported by P42ES010337, S.B.H. by Veterans Affairs Research Service, E.S. by R01AA020172, R01DK085252 and P42ES010337, and F.M. by NIH HL091061.

PY - 2014/7/21

Y1 - 2014/7/21

N2 - 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.

AB - 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.

KW - Cell signalling

KW - Liver fibrosis

KW - Pathogenesis

U2 - 10.1038/ncomms5451

DO - 10.1038/ncomms5451

M3 - Article

C2 - 25043713

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4451

ER -

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

Abstract

Bibliographical note

Keywords

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