Wang Changhua, Xin Xiaoban, Xiang Ruihua, Ramos Fresnida J, Liu Meilian, Lee Hak Joo, Chen Hongzhi, Mao Xuming, Kikani Chintan K, Liu Feng, Dong Lily Q
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
J Biol Chem. 2009 Nov 13;284(46):31608-15. doi: 10.1074/jbc.M109.010355. Epub 2009 Aug 6.
APPL1 is a newly identified adiponectin receptor-binding protein that positively mediates adiponectin signaling in cells. Here we report that APPL2, an isoform of APPL1 that forms a dimer with APPL1, can interacts with both AdipoR1 and AdipoR2 and acts as a negative regulator of adiponectin signaling in muscle cells. Overexpression of APPL2 inhibits the interaction between APPL1 and AdipoR1, leading to down-regulation of adiponectin signaling in C2C12 myotubes. In contrast, suppressing APPL2 expression by RNAi significantly enhances adiponectin-stimulated glucose uptake and fatty acid oxidation. In addition to targeting directly to and competing with APPL1 in binding with the adiponectin receptors, APPL2 also suppresses adiponectin and insulin signaling by sequestrating APPL1 from these two pathways. In addition to adiponectin, metformin also induces APPL1-APPL2 dissociation. Taken together, our results reveal that APPL isoforms function as an integrated Yin-Yang regulator of adiponectin signaling and mediate the cross-talk between adiponectin and insulin signaling pathways in muscle cells.
APPL1是一种新发现的脂联素受体结合蛋白，可在细胞中正向介导脂联素信号传导。在此我们报告，APPL2作为APPL1的一种异构体，可与APPL1形成二聚体，它能与AdipoR1和AdipoR2相互作用，并在肌肉细胞中作为脂联素信号传导的负调节因子发挥作用。APPL2的过表达会抑制APPL1与AdipoR1之间的相互作用，导致C2C12肌管中脂联素信号传导的下调。相反，通过RNA干扰抑制APPL2的表达可显著增强脂联素刺激的葡萄糖摄取和脂肪酸氧化。除了直接靶向并与APPL1竞争结合脂联素受体外，APPL2还通过将APPL1从这两条途径中隔离出来，抑制脂联素和胰岛素信号传导。除脂联素外，二甲双胍也可诱导APPL1-APPL2解离。综上所述，我们的结果表明，APPL异构体作为脂联素信号传导的综合阴阳调节因子，介导肌肉细胞中脂联素和胰岛素信号通路之间的相互作用。
