钙调蛋白依赖性蛋白激酶激酶β-腺苷酸活化蛋白激酶信号复合物的特性研究。
Characterization of the CaMKKβ-AMPK signaling complex.
机构信息
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27713, USA.
出版信息
Cell Signal. 2011 Dec;23(12):2005-12. doi: 10.1016/j.cellsig.2011.07.014. Epub 2011 Jul 23.
The AMP-activated protein kinase (AMPK) is a critical regulator of energy homeostasis, and is a potential target for treatment of metabolic diseases as well as cancer. AMPK can be phosphorylated and activated by the tumor suppressor LKB1 or the Ca(2+)/CaM-dependent protein kinase kinase β (CaMKKβ). We previously identified a physical complex between CaMKKβ and AMPK (Anderson, K. A., Ribar, T. J., Lin, F., Noeldner, P. K., Green, M. F., Muehlbauer, M. J., Witters, L. A., Kemp, B. E., and Means, A. R. (2008) Cell Metabolism 7, 377-388). Here we expand our analysis of the CaMKKβ-AMPK signaling complex and show that whereas CaMKKβ can form a complex with and activate AMPK, CaMKKα cannot. In addition, we show that CaMKKβ and AMPK associate through their kinase domains, and CaMKKβ must be in an active conformation in order to bind AMPK but not to associate with an alternative substrate, Ca(2+)/Calmodulin-dependent protein kinase IV (CaMKIV). Our results demonstrate that CaMKKβ and AMPK form a unique signaling complex. This raises the possibility that the CaMKKβ-AMPK complex can be specifically targeted by small molecule drugs to treat disease.
AMP 激活的蛋白激酶（AMPK）是能量平衡的关键调节剂，也是治疗代谢性疾病和癌症的潜在靶点。AMPK 可以被肿瘤抑制因子 LKB1 或 Ca(2+)/CaM 依赖性蛋白激酶激酶β（CaMKKβ）磷酸化和激活。我们之前发现了 CaMKKβ 和 AMPK 之间的物理复合物（Anderson, K. A., Ribar, T. J., Lin, F., Noeldner, P. K., Green, M. F., Muehlbauer, M. J., Witters, L. A., Kemp, B. E., and Means, A. R. (2008) Cell Metabolism 7, 377-388）。在这里，我们扩展了对 CaMKKβ-AMPK 信号复合物的分析，并表明 CaMKKβ 可以形成复合物并激活 AMPK，而 CaMKKα 则不能。此外，我们还表明 CaMKKβ 和 AMPK 通过其激酶结构域结合，并且 CaMKKβ 必须处于活性构象才能结合 AMPK，但不能与替代底物 Ca(2+)/钙调蛋白依赖性蛋白激酶 IV（CaMKIV）结合。我们的结果表明 CaMKKβ 和 AMPK 形成了一个独特的信号复合物。这增加了一种可能性，即 CaMKKβ-AMPK 复合物可以被小分子药物特异性靶向，以治疗疾病。
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