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

• Published in: The Journal of biological chemistry Vol. 291; no. 16; pp. 8399 - 8413
• Main Authors: Nakhaei-Rad, Saeideh, Nakhaeizadeh, Hossein, Götze, Silke, Kordes, Claus, Sawitza, Iris, Hoffmann, Michèle J, Franke, Manuel, Schulz, Wolfgang A., Scheller, Jürgen, Piekorz, Roland P., Häussinger, Dieter, Ahmadian, Mohammad R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell Biology; DNA Methylation - physiology; embryonic stem cell; embryonic stem cell-expressed RAS; embryonic stem cell-expressed RAS, ERAS; embryonic stem cell-expressed RAS, ERAS, AKT; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; hepatic stellate cell (HSC); Hepatic Stellate Cells - cytology; Hepatic Stellate Cells - enzymology; Hippo pathway; Male; mammalian target of rapamycin (mTOR); MAP Kinase Signaling System - physiology; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oncogene Protein p21(ras) - biosynthesis; Oncogene Protein p21(ras) - genetics; phosphatidylinositide 3-kinase (PI 3-kinase); Promoter Regions, Genetic - physiology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Raf kinase; Rats; Rats, Wistar; signal transduction; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; embryonic stem cell-expressed RAS, ERAS; Hippo pathway; embryonic stem cell; hepatic stellate cell (HSC); signal transduction; mammalian target of rapamycin (mTOR); embryonic stem cell-expressed RAS; embryonic stem cell-expressed RAS, ERAS, AKT; Raf kinase; phosphatidylinositide 3-kinase (PI 3-kinase)
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M115.700088

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.