Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.
Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.
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DOI：
10.1038/s41419-022-04801-0
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发表时间：
2022-04-29
影响因子：
9
通讯作者：
Piao, Hai-long
中科院分区：
文献类型：
--
作者：
Xia, Tian;Chen, Di;Liu, Xiaolong;Qi, Huan;Wang, Wen;Chen, Huan;Ling, Ting;Otkur, Wuxiyar;Zhang, Chen-Song;Kim, Jongchan;Lin, Sheng-Cai;Piao, Hai-long
中期因子（MDK）是一种分泌性生长因子，通过与受体相互作用调节信号转导和肿瘤进展，并可通过胞吞作用内化至细胞质中。然而，它的细胞内功能和信号调节仍然不清楚。在这里，我们表明细胞内MDK与LKB 1和STRAD相互作用，破坏LKB 1-STRAD-Mo 25复合物。因此，MDK降低了LKB 1的活性，以抑制葡萄糖饥饿或2-DG处理引起的AMPK的基础和应激诱导的激活。我们还发现MDK通过抑制LKB 1-AMPK轴的激活来加速癌细胞增殖。在人类癌症中，与其他众所周知的生长因子相比，MDK表达在癌症中最显著上调，特别是在肝癌、肾癌和乳腺癌中，与临床结果相关，并与磷酸化AMPK水平负相关。我们的研究阐明了AMPK激活的抑制机制，这是由细胞内MDK通过破坏LKB 1-STRAD-Mo 25复合物介导的。
Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.
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