Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
FASEB J. 2019 Feb;33(2):2957-2970. doi: 10.1096/fj.201801225R. Epub 2018 Oct 18.
AMPK is a crucial regulator of energy homeostasis that acts downstream of its upstream kinase liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase 2 (CaMKK2). LKB1 primarily phosphorylates AMPK after energy stress, whereas calcium-mediated activation of AMPK requires CaMKK2, although the regulatory mechanisms of calcium-mediated AMPK activation remain unclear. Using biochemical, microscopic, and genetic approaches, we demonstrate that the stromal interaction molecule (STIM)2, a calcium sensor, acts as a novel regulator of CaMKK2-AMPK signaling. We reveal that STIM2 interacts with AMPK and CaMKK2 and that the increase in intracellular calcium levels promotes AMPK colocalization and interaction with STIM2. We further show that STIM2 deficiency attenuates calcium-induced but not energy stress-induced AMPK activation, possibly by regulating the CaMKK2-AMPK interaction. Together, our results identify a previously unappreciated mechanism that modulates calcium-mediated AMPK activation.-Chauhan, A. S., Liu, X., Jing, J., Lee, H., Yadav, R. K., Liu, J., Zhou, Y., Gan B. STIM2 interacts with AMPK and regulates calcium-induced AMPK activation.
AMPK 是能量平衡的关键调节剂，其作用位于上游激酶肝激酶 B1（LKB1）和钙/钙调蛋白依赖性蛋白激酶 2（CaMKK2）的下游。在能量应激后，LKB1 主要磷酸化 AMPK，而钙介导的 AMPK 激活需要 CaMKK2，尽管钙介导的 AMPK 激活的调节机制仍不清楚。我们使用生化、显微镜和遗传方法证明，钙传感器基质相互作用分子（STIM）2 是 CaMKK2-AMPK 信号的新型调节剂。我们揭示了 STIM2 与 AMPK 和 CaMKK2 相互作用，并且细胞内钙水平的增加促进 AMPK 共定位和与 STIM2 的相互作用。我们进一步表明，STIM2 缺乏会减弱钙诱导但不会减弱能量应激诱导的 AMPK 激活，可能通过调节 CaMKK2-AMPK 相互作用来实现。总之，我们的结果确定了一种以前未被认识的调节钙介导的 AMPK 激活的机制。-Chauhan，A. S.，Liu，X.，Jing，J.，Lee，H.，Yadav，R. K.，Liu，J.，Zhou，Y.，Gan B. STIM2 与 AMPK 相互作用并调节钙诱导的 AMPK 激活。
