CHIP‐dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response |
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| Authors: | Takeshi Maruyama Hisae Kadowaki Noriaki Okamoto Atsushi Nagai Isao Naguro Atsushi Matsuzawa Hiroshi Shibuya Keiji Tanaka Shigeo Murata Kohsuke Takeda Hideki Nishitoh Hidenori Ichijo |
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| Affiliation: | 1. Department of Medical Pharmaceutics, Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Global Center of Excellence Program and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan;2. Department of Molecular Cell Biology, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Bunkyo‐ku, Tokyo, Japan;3. Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Setagaya‐ku, Tokyo, Japan;4. Department of Integrated Biology, Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo‐ku, Tokyo, Japan |
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| Abstract: | The extracellular signal‐regulated kinase (ERK) pathway is an important signalling pathway that regulates a large number of cellular processes, including proliferation, differentiation and gene expression. Hyperosmotic stress activates the ERK pathway, whereas little is known about the regulatory mechanisms and physiological functions of ERK activation in hyperosmotic response. Here, we show that MAPK/ERK kinase kinase 2 (MEKK2), a member of the MAPKKK family, mediated the specific and transient activation of ERK, which was required for the induction of aquaporin 1 (AQP1) and AQP5 gene expression in response to hyperosmotic stress. Moreover, we identified the E3 ubiquitin ligase carboxyl terminus of Hsc70‐interacting protein (CHIP) as a binding partner of MEKK2. Depletion of CHIP by small‐interference RNA or gene targeting attenuated the degradation of MEKK2 and prolonged the ERK activity. Interestingly, hyperosmolality‐induced gene expression of AQP1 and AQP5 was suppressed by CHIP depletion and was reversed by inhibition of the prolonged phase of ERK activity. These findings show that transient activation of the ERK pathway, which depends not only on MEKK2 activation, but also on CHIP‐dependent MEKK2 degradation, is crucial for proper gene expression in hyperosmotic stress response. |
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| Keywords: | CHIP hyperosmotic stress MEKK2 ubiquitin‐proteasomal degradation |
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