Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance
Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance
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DOI：
10.1073/pnas.0703650104
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发表时间：
2007-08-21
影响因子：
11.1
通讯作者：
Inokuchi, Jin-ichi
中科院分区：
文献类型：
--
作者：
Kabayama, Kazuya;Sato, Takashige;Inokuchi, Jin-ichi
膜微区（脂筏）现在被认为是胰岛素信号传导正确区室化的关键。我们先前证明，在TNF α诱导的胰岛素抵抗状态下的脂肪细胞中，胰岛素代谢信号的抑制和小窝微区胰岛素受体（1111）的消除与神经节苷脂GM 3的积累有关。为了深入了解IR，小窝蛋白-1（Cavl）和GM 3在脂肪细胞中相互作用的分子机制，我们进行了免疫沉淀，IR和GM 3的交联研究，以及使用全内反射荧光显微镜和光漂白技术后荧光恢复的活细胞研究。我们发现：（i）IR独立地与Cav 1和GM 3形成复合物;（h）在富含GM 3的膜中，IR的迁移率通过IR-Cav 1相互作用的解离而增加;以及（iii）位于IR β亚基的跨膜结构域上方的赖氨酸残基对于IR与GM 3的相互作用是必需的。由于已知脂肪细胞中的胰岛素代谢信号转导严重依赖于小窝，因此我们提出了由IR与GM 3在微区中的相互作用引起的IR-Cavl复合物的解离引起的脂肪细胞中胰岛素抵抗的病理特征。
Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling. We previously demonstrated that, in adipocytes in a state of TNF alpha-induced insulin resistance, the inhibition of insulin metabolic signaling and the elimination of insulin receptors (1111) from the caveolae microdomains were associated with an accumulation of the ganglioside GM3. To gain insight into molecular mechanisms behind interactions of IR, caveolin-1 (Cavl), and GM3 in adipocytes, we have performed immunoprecipitations, cross-linking studies of IR and GM3, and live cell studies using total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching techniques. We found that (i) IR form complexes with Cav1 and GM3 independently; (h) in GM3-enriched membranes the mobility of IR is increased by dissociation of the IR-Cav1 interaction; and (iii) the lysine residue localized just above the transmembrane domain of the IR beta-subunit is essential for the interaction of IR with GM3. Because insulin metabolic signal transduction in adipocytes is known to be critically dependent on caveolae, we propose a pathological feature of insulin resistance in adipocytes caused by dissociation of the IR-Cavl complex by the interactions of IR with GM3 in microdomains.