title: MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species.
abstract: Reactive oxygen species (ROS) influence diverse cellular processes, including proliferation and apoptosis. Both endogenous and exogenous ROS activate signaling through mitogen-activated proteins kinase (MAPK) pathways, including those involving extracellular signal-regulated kinases (ERKs) or c-Jun N-terminal kinases (JNKs). Whereas low concentrations of ROS generally stimulate proliferation, high concentrations result in cell death. We found that low concentrations of ROS induced activating phosphorylation of ERKs, whereas high concentrations of ROS induced activating phosphorylation of JNKs. Mixed lineage kinase 3 (MLK3, also known as MAP3K11) directly phosphorylates JNKs and may control activation of ERKs. Mathematical modeling of MAPK networks revealed a positive feedback loop involving MLK3 that determined the relative phosphorylation of ERKs and JNKs by ROS. Cells exposed to an MLK3 inhibitor or cells in which MLK3 was knocked down showed increased activation of ERKs and decreased activation of JNKs and were resistant to cell death when exposed to high concentrations of ROS. Thus, the data indicated that MLK3 is a critical factor controlling the activity of kinase networks that control the cellular responses to different concentrations of ROS.
authors.affiliation: Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Ho-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Hwang
authors.affiliation: Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea. ckh@kaist.ac.kr kwonks@kribb.re.kr.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
authors.affiliation: Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. ckh@kaist.ac.kr kwonks@kribb.re.kr.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013778:Tetrazolium Salts; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C110656:2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium