GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis.
GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis.
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DOI：
10.1038/ncomms5451
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发表时间：
2014-07-21
影响因子：
16.6
通讯作者：
Ghosh, Pradipta
中科院分区：
文献类型：
--
作者：
Lopez-Sanchez, Inmaculada;Lopez-Sanchez, Inmaculada;Dunkel, Ying;Roh, Yoon-Seok;Mittal, Yash;De Minicis, Samuele;Muranyi, Andrea;Singh, Shalini;Shanmugam, Kandavel;Aroonsakool, Nakon;Murray, Fiona;Ho, Samuel B.;Seki, Ekihiro;Brenner, David A.;Ghosh, Pradipta
进行性肝纤维化的特征在于通过活化的肝星状细胞（HSC）的胶原沉积。HSC的激活是一个多受体驱动的过程，其中促纤维化信号增强，抗纤维化途径受到抑制。在这里，我们报告了一个新的信号平台的发现，包括G蛋白亚基，Gαi和GIV，其鸟嘌呤交换因子（GEF），作为一个中心枢纽内的纤维化信号网络启动的不同类别的受体。GIV在纤维化损伤后在肝脏中表达，并且是HSC活化所需的。一旦表达，GIV增强促纤维化（PI 3 K-Akt-FoxO 1和TGFβ-SMAD）并抑制抗纤维化（cAMP-PKA-pCREB）途径，使信号网络偏向纤维化，所有这些都是通过激活Gαi。我们还提供了证据表明，GIV可以作为肝损伤后纤维化进展的生物标志物，以及在肝纤维化期间阻止和/或逆转HSC活化的治疗靶点。
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 anti-fibrotic pathways are suppressed. Here we report the discovery of a novel signaling platform comprised of 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 anti-fibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favor 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.
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