Cell Biology
The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells*

https://doi.org/10.1074/jbc.M115.700088Get rights and content
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Hepatic stellate cells (HSCs) were recently identified as liver-resident mesenchymal stem cells. HSCs are activated after liver injury and involved in pivotal processes, such as liver development, immunoregulation, regeneration, and also fibrogenesis. To date, several studies have reported candidate pathways that regulate the plasticity of HSCs during physiological and pathophysiological processes. Here we analyzed the expression changes and activity of the RAS family GTPases and thereby investigated the signaling networks of quiescent HSCs versus activated HSCs. For the first time, we report that embryonic stem cell-expressed RAS (ERAS) is specifically expressed in quiescent HSCs and down-regulated during HSC activation via promoter DNA methylation. Notably, in quiescent HSCs, the high level of ERAS protein correlates with the activation of AKT, STAT3, mTORC2, and HIPPO signaling pathways and inactivation of FOXO1 and YAP. Our data strongly indicate that in quiescent HSCs, ERAS targets AKT via two distinct pathways driven by PI3Kα/δ and mTORC2, whereas in activated HSCs, RAS signaling shifts to RAF-MEK-ERK. Thus, in contrast to the reported role of ERAS in tumor cells associated with cell proliferation, our findings indicate that ERAS is important to maintain quiescence in HSCs.

embryonic stem cell
hepatic stellate cell (HSC)
Hippo pathway
mammalian target of rapamycin (mTOR)
phosphatidylinositide 3-kinase (PI 3-kinase)
Raf kinase
signal transduction
embryonic stem cell-expressed RAS
embryonic stem cell-expressed RAS, ERAS
embryonic stem cell-expressed RAS, ERAS, AKT

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*

This work was supported by the Deutsche Forschungsgemeinschaft through Collaborative Research Center 974 ( SFB 974 ), “Communication and System Relevance during Liver Injury and Regeneration.” The authors declare that they have no conflicts of interest with the contents of this article.

This article contains supplemental Table S1 and Figs. S1–S4.