Yin-Yang Regulation of Adiponectin Signaling by APPL Isoforms in Muscle Cells
Yin-Yang Regulation of Adiponectin Signaling by APPL Isoforms in Muscle Cells
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DOI：
10.1074/jbc.m109.010355
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发表时间：
2009-11-13
影响因子：
4.8
通讯作者：
Dong, Lily Q.
中科院分区：
文献类型：
--
作者：
Wang, Changhua;Xin, Xiaoban;Dong, Lily Q.
APPL1是新近发现的一种脂联素受体结合蛋白，可在细胞内积极介导脂联素信号转导。APPL2是APPL1的一个亚型，与APPL1形成二聚体，可与AdipoR1和AdipoR2相互作用，并在肌肉细胞中作为脂联素信号的负调节因子。APPL2的过表达抑制了APPL1和AdipoR1之间的相互作用，导致C2C12肌管中脂联素信号的下调。相反，通过RNAi抑制APPL2的表达显著增强了脂联素刺激的葡萄糖摄取和脂肪酸氧化。除了直接靶向APPL1并与APPL1竞争与脂联素受体结合外，APPL2还通过阻断APPL1的这两条途径抑制脂联素和胰岛素信号转导。除脂联素外，二甲双胍还可诱导APPL1-APPL2解离。综上所述，我们的结果表明，APPL亚型作为脂联素信号的阴阳调节因子，在肌肉细胞中介导了脂联素和胰岛素信号通路之间的串扰。
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 crosstalk between adiponectin and insulin signaling pathways in muscle cells.