Journal of Biological Chemistry, Volume (291), No (16), Year (2016-4) , Pages (8399-8413)

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

Authors: Saeideh Nakhaeirad , Hossein Nakhaeizadeh , Silke Gotze , Claus Kordes , Iris Sawitza , Michele J Hoffmann , Manuel Franke , Wolfgang A. Schulz , Jurgen Scheller , Roland P. Piekorz , Dieter Haussinger , Mohammad R. Ahmadian ,

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Abstract

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.

Keywords

, Hippo pathway; Raf kinase; embryonic stem cell; embryonic stem cell-expressed RAS; embryonic stem cell-expressed RAS, ERAS; embryonic stem cell-expressed RAS, ERAS, AKT; hepatic stellate cell (HSC); mammalian target of rapamycin (mTOR); phosphatidylinositide 3-kinase (PI 3-kinase); signal transducti
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@article{paperid:1077935,
author = {Nakhaeirad, Saeideh and Hossein Nakhaeizadeh and Silke Gotze and Claus Kordes and Iris Sawitza and Michele J Hoffmann and Manuel Franke and Wolfgang A. Schulz and Jurgen Scheller and Roland P. Piekorz and Dieter Haussinger and Mohammad R. Ahmadian},
title = {The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells},
journal = {Journal of Biological Chemistry},
year = {2016},
volume = {291},
number = {16},
month = {April},
issn = {0021-9258},
pages = {8399--8413},
numpages = {14},
keywords = {Hippo pathway; Raf kinase; embryonic stem cell; embryonic stem cell-expressed RAS; embryonic stem cell-expressed RAS; ERAS; embryonic stem cell-expressed RAS; ERAS; AKT; hepatic stellate cell (HSC); mammalian target of rapamycin (mTOR); phosphatidylinositide 3-kinase (PI 3-kinase); signal transduction},
}

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%0 Journal Article
%T The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells
%A Nakhaeirad, Saeideh
%A Hossein Nakhaeizadeh
%A Silke Gotze
%A Claus Kordes
%A Iris Sawitza
%A Michele J Hoffmann
%A Manuel Franke
%A Wolfgang A. Schulz
%A Jurgen Scheller
%A Roland P. Piekorz
%A Dieter Haussinger
%A Mohammad R. Ahmadian
%J Journal of Biological Chemistry
%@ 0021-9258
%D 2016

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