APPL1 Mediates Adiponectin-Induced LKB1 Cytosolic Localization Through the PP2A-PKCζ Signaling Pathway
APPL1 Mediates Adiponectin-Induced LKB1 Cytosolic Localization Through the PP2A-PKCζ Signaling Pathway
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DOI：
10.1210/me.2011-0082
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发表时间：
2011-10-01
影响因子：
--
通讯作者：
Dong, Lily Q.
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文献类型：
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作者：
Deepa, Sathyaseelan S.;Zhou, Lijun;Dong, Lily Q.
我们最近发现含有pleckstrin同源结构域、磷酸酪氨酸结合结构域和亮氨酸拉链基序（APPL）1的衔接蛋白是介导脂联素信号诱导肝激酶B 1（LKB）1胞浆转位的关键，而LKB 1胞浆转位是细胞内AMP活化蛋白激酶（AMPK）活化的关键步骤。然而，其潜在的分子机制仍然未知。在这里，我们证明，脂联素处理C2 C12肌管促进APPL 1与蛋白磷酸酶2A（PP 2A）和蛋白激酶C ζ（PKC ζ）的相互作用，导致PP 2A的激活和随后的去磷酸化和PKC ζ的失活。脂联素诱导的PKC zeta失活导致LKB 1在Ser（307）处的去磷酸化及其随后的易位至胞质溶胶，在胞质溶胶中其刺激AMPK活性。有趣的是，我们发现二甲双胍也诱导LKB 1胞质易位，但这种刺激不依赖于APPL 1和PP 2A-PKC zeta通路。总之，我们的研究揭示了脂联素刺激肌肉细胞中AMPK活化的新机制，并揭示了预防和治疗胰岛素抵抗及其相关疾病的潜在靶点。（分子内分泌学25：1773-1785，2011）
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 C zeta (PKC zeta), leading to the activation of PP2A and subsequent dephosphorylation and inactivation of PKC zeta. The adiponectin-induced inactivation of PKC zeta 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-PKC zeta 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. (Molecular Endocrinology 25: 1773-1785, 2011)