title: The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells.
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.
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty.
authors.forename: Saeideh
authors.initials: S
authors.lastname: Nakhaei-Rad
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty.
authors.forename: Hossein
authors.initials: H
authors.lastname: Nakhaeizadeh
authors.affiliation: the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and.
authors.forename: Silke
authors.initials: S
authors.lastname: Götze
authors.affiliation: the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and.
authors.forename: Claus
authors.initials: C
authors.lastname: Kordes
authors.affiliation: the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and.
authors.forename: Iris
authors.initials: I
authors.lastname: Sawitza
authors.affiliation: the Department of Urology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany.
authors.forename: Michèle J
authors.initials: MJ
authors.lastname: Hoffmann
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty.
authors.forename: Manuel
authors.initials: M
authors.lastname: Franke
authors.affiliation: the Department of Urology, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schulz
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.affiliation: the Clinic of Gastroenterology, Hepatology, and Infectious Diseases, and.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: From the Institute of Biochemistry and Molecular Biology II, Medical Faculty, reza.ahmadian@uni-duesseldorf.de.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ahmadian
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000071161:Forkhead Box Protein O1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051858:Forkhead Transcription Factors; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D015689:Oncogene Protein p21(ras); D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
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