Deepa Sathyaseelan S, Zhou Lijun, Ryu Jiyoon, Wang Changhua, Mao Xuming, Li Cai, Zhang Ning, Musi Nicolas, DeFronzo Ralph A, Liu Feng, Dong Lily Q
Department of Cellular and Structural Biology, University of Texas Health Science Centre at San Antonio, San Antonio, Texas 78229-3900, USA.
Mol Endocrinol. 2011 Oct;25(10):1773-85. doi: 10.1210/me.2011-0082. Epub 2011 Aug 11.
We recently found that the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL)1 is essential for mediating adiponectin signal to induce liver kinase B (LKB)1 cytosloic translocation, an essential step for activation of AMP-activated protein kinase (AMPK) in cells. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that treating C2C12 myotubes with adiponectin promoted APPL1 interaction with protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ), leading to the activation of PP2A and subsequent dephosphorylation and inactivation of PKCζ. The adiponectin-induced inactivation of PKCζ results in dephosphorylation of LKB1 at Ser(307) and its subsequent translocation to the cytosol, where it stimulates AMPK activity. Interestingly, we found that metformin also induces LKB1 cytosolic translocation, but the stimulation is independent of APPL1 and the PP2A-PKCζ pathway. Together, our study uncovers a new mechanism underlying adiponectin-stimulated AMPK activation in muscle cells and shed light on potential targets for prevention and treatment of insulin resistance and its associated diseases.
我们最近发现，含普列克底物蛋白同源结构域、磷酸酪氨酸结合结构域和亮氨酸拉链模体的衔接蛋白（APPL）1对于介导脂联素信号以诱导肝激酶B（LKB）1的胞质易位至关重要，而这是细胞中激活AMP活化蛋白激酶（AMPK）的关键步骤。然而，其潜在的分子机制仍不清楚。在此，我们证明用脂联素处理C2C12肌管可促进APPL1与蛋白磷酸酶2A（PP2A）和蛋白激酶Cζ（PKCζ）相互作用，导致PP2A激活以及PKCζ随后的去磷酸化和失活。脂联素诱导的PKCζ失活导致LKB1在Ser（307）位点去磷酸化及其随后向胞质的易位，在胞质中它刺激AMPK活性。有趣的是，我们发现二甲双胍也可诱导LKB1的胞质易位，但这种刺激独立于APPL1和PP2A-PKCζ途径。总之，我们的研究揭示了肌肉细胞中脂联素刺激AMPK激活的一种新机制，并为预防和治疗胰岛素抵抗及其相关疾病的潜在靶点提供了线索。
