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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Ekih, 2014. "GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis," Nature Communications, Nature, vol. 5(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5451
    DOI: 10.1038/ncomms5451
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