Z Gastroenterol 2015; 53 - A1_20
DOI: 10.1055/s-0035-1567950

Expression, epigenetical regulation and signaling network of embryonic stem cell-expressed RAS in hepatic stellate cells

S Nakhaei-Rad 1, H Nakhaeizadeh 1, S Götze 2, C Kordes 2, D Häussinger 2, MR Ahmadian 1
  • 1Heinrich-Heine University, Institute of Biochemistry and Molecular Biology II, Düsseldorf, Deutschland
  • 2Heinrich-Heine University, Clinic of Gastroenterology, Hepatology and Infectious Diseases, Düsseldorf, Deutschland

Hepatic stellate cells (HSC) are liver-resident mesenchymal stem cells with progenitor characteristics. HSCs are activated during liver injury and are involved in pivotal processes e.g. liver development, immunoregulation, regeneration and also fibrosis [1,2]. To date, several controversial studies reported the candidate pathways that regulate the plasticity of HSC towards distinct physiological and pathophysiological processes. Here we analyzed the expressional changes and activity of small GTPases of the RAS family, and investigated the signaling networks of quiescent HSC versus activated HSC. For the first time, we report that embryonic stem cell-expressed RAS (ERAS) [3] is specifically expressed amongst the liver cells in quiescent primary HSCs and downregulated in the course of culture-induced HSC activation dues to promoter DNA methylation. Notably, the high level of the ERAS protein correlates with the activation of mTORC2, AKT, and HIPPO in quiescent HSCs. We showed that RAS signaling in activated HSC is more towards RAF-MEK-ERK pathway while quiescent HSC rely on the AKT activation, which may in turn result from an ERAS-derived activation of PI3K and mTORC2 pathways. These and other mechanisms controlling the HSC fate/function will be discussed.

References:

[1] Kordes, C. & Häussinger, D. Hepatic stem cell niches. Journal of Clinical Investigation 123, 1874 – 1880 (2013).

[2] Kordes, C., Sawitza, I., Götze, S., Herebian, D. & Häussinger, D. Hepatic stellate cells contribute to progenitor cells and liver regeneration. Journal of Clinical Investigation 124, 5503 – 5515 (2014).

[3] Nakhaei-Rad, S., Nakhaeizadeh, H., Kordes, C., Cirstea, I.C., Schmick, M., Dvorsky, R., Bastiaens, P.I., Haussinger, D. & Ahmadian, M.R. The function of embryonic stem cell-expressed Ras (E-Ras), a unique Ras family member, correlates with its additional motifs and its structural properties. J Biol Chem (2015).

Corresponding author: Ahmadina, Mohammad Reza

E-Mail: Reza.Ahmadian@uni-duesseldorf.de