CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response
CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response
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DOI：
10.1038/emboj.2010.141
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发表时间：
2010-08-04
期刊：
影响因子：
11.4
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
--
作者：
Maruyama, Takeshi;Kadowaki, Hisae;Ichijo, Hidenori
细胞外信号调节激酶（ERK）通路是调节大量细胞过程的重要信号通路，包括增殖、分化和基因表达。高渗应激激活ERK通路，但人们对高渗反应中ERK激活的调节机制和生理功能知之甚少。在这里，我们发现 MAPK/ERK 激酶激酶 2 (MEKK2)（MAPKKK 家族的成员）介导 ERK 的特异性和瞬时激活，这是诱导水通道蛋白 1 (AQP1) 和 AQP5 基因表达以响应高渗应激所必需的。此外，我们鉴定了 Hsc70 相互作用蛋白 (CHIP) 的 E3 泛素连接酶羧基末端作为 MEKK2 的结合伴侣。通过小干扰 RNA 或基因靶向消除 CHIP 可减弱 MEKK2 的降解并延长 ERK 活性。有趣的是，高渗透压诱导的 AQP1 和 AQP5 基因表达受到 CHIP 消耗的抑制，并通过抑制 ERK 活性的延长期而逆转。这些发现表明，ERK 通路的瞬时激活不仅取决于 MEKK2 激活，还取决于 CHIP 依赖性 MEKK2 降解，对于高渗应激反应中正确的基因表达至关重要。 EMBO 杂志 (2010) 29, 2501-2514。 doi：10.1038/emboj.2010.141； 2010 年 6 月 29 日在线发布
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. The EMBO Journal (2010) 29, 2501-2514. doi:10.1038/emboj.2010.141; Published online 29 June 2010