MLK3 phophorylates AMPK independently of LKB1.
MLK3 phophorylates AMPK independently of LKB1.
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MLK3 独立于 LKB1 磷酸化 AMPK
DOI：
10.1371/journal.pone.0123927
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Luo Z
中科院分区：
文献类型：
--
作者：
Luo L;Jiang S;Huang D;Lu N;Luo Z
新的证据表明，细胞能量代谢受AMPK和MLK3-JNK信号通路的调控，但它们之间的功能联系尚不清楚。本研究旨在探讨MLK3和AMPK之间的串扰。我们发现JNK和AMPK在它们的激活位点被TNF-α、大霉素、H2O2和山梨醇磷酸化。有趣的是，山梨醇刺激了lkb1缺陷细胞中AMPK在T172位点的磷酸化。在筛选了100多个激酶后，我们发现MLK3诱导AMPK在T172位点磷酸化。我们的体外分析进一步发现，mlk3介导的AMPK在T172位点的磷酸化与AMP无关，但AMP的加入导致AMPK的迁移性转移，这是自磷酸化的一个迹象，表明AMP与T172的结合和磷酸化导致AMPK的最大激活。GST-pull - down实验显示AMPKα1亚基与MLK3之间存在直接相互作用。总之，我们的研究结果表明，MLK3作为AMPK和JNK的共同上游激酶，独立于LKB1作为AMPK的直接上游激酶。
Emerging evidence has shown that cellular energy metabolism is regulated by the AMPK and MLK3-JNK signaling pathways, but the functional link between them remains to be determined. The present study aimed to explore the crosstalk between MLK3 and AMPK. We found that both JNK and AMPK were phosphorylated at their activation sites by TNF-α, Anisomycin, H2O2 and sorbitol. Interestingly, sorbitol stimulated phosphorylation of AMPK at T172 in LKB1-deficient cells. Following the screening of more than 100 kinases, we identified that MLK3 induced phosphorylation of AMPK at T172. Our in vitro analysis further revealed that MLK3-mediated phosphorylation of AMPK at T172 was independent of AMP, but addition of AMP caused a mobility shift of AMPK, an indication of autophosphorylation, suggesting that AMP binding and phosphorylation of T172 leads to maximal activation of AMPK. GST-pull down assays showed a direct interaction between AMPKα1 subunit and MLK3. Altogether, our results indicate that MLK3 serves as a common upstream kinase of AMPK and JNK and functions as a direct upstream kinase for AMPK independent of LKB1.
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