GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation
GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation
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DOI：
10.1111/j.1471-4159.2010.06930.x
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发表时间：
2010-10-01
影响因子：
4.7
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
--
作者：
Higashi, Shinji;Iseki, Eizo;Wada, Keiji
GIGYF 2已被报道为PARK 11连锁帕金森病（PD）的候选基因。GIGYF 2的杂合敲除导致神经变性，表明GIGYF 2（Grb 10相互作用GYF蛋白2）在CNS中的重要作用。在这项研究中，我们使用新的GIGYF 2抗体来阐明GIGYF 2的分布和功能。GIGYF 2广泛表达，在胰腺和睾丸中表达最高，在脑、肺、肝、肾和脾中表达中等。在脑中，GIGYF 2与S3部分中的膜紧密相关，并且定位于神经元胞体和近端树突中。免疫组织化学分析表明，GIGYF 2定位于整个小鼠大脑，在大脑皮质、海马、小脑、嗅球和脑干核中含量较高，但在黑质和纹状体中含量较低。GIGYF 2存在于Rab 4和Grb 10免疫阳性的核内体中。GIGYF 2的表达改变了胰岛素样生长因子-1（IGF-1）受体的运输，并增强了IGF-1诱导的细胞外信号调节激酶1/2磷酸化，但没有IGF-1受体或丝氨酸/苏氨酸蛋白激酶Akt磷酸化。在表达野生型和假定的PD相关突变体GIGYF 2的细胞之间，信号传导活化没有显著差异。在PD脑中，GIGYF 2没有定位于路易体。我们的研究结果表明GIGYF 2在调节内体信号传导中的作用，但GIGYF 2对PD的发病机制没有贡献。
GIGYF2 has been reported as a candidate gene for PARK11-linked Parkinson's disease (PD). Heterozygous knockout of GIGYF2 results in neurodegeneration, suggesting important roles for GIGYF2 (Grb10 interacting GYF protein 2) in the CNS. In this study, we used novel GIGYF2 antibodies to clarify the distribution and function of GIGYF2. GIGYF2 was widely expressed, most highly in the pancreas and testis, and moderately in brain, lung, liver, kidney and spleen. In the brain, GIGYF2 was tightly associated with membrane in the S3 fraction, and localised in neuronal perikarya and proximal dendrites. Immunohistochemical analysis indicated sites of GIGYF2 localisation throughout the mouse brain, with high levels in the cerebral cortex, hippocampus, cerebellum, olfactory bulb and brainstem nuclei, but low levels in the substantia nigra and striatum. GIGYF2 was present in endosomes immunopositive for Rab4 and Grb10. Expression of GIGYF2 altered insulin-like growth factor-1 (IGF-1) receptor trafficking and enhanced IGF-1-induced extracellular signal-regulated kinase 1/2 phosphorylation, but not IGF-1 receptor or serine/threonine protein kinase Akt phosphorylation. There were no significant differences in signalling activation between cells expressing wild-type and putative PD-associated mutant GIGYF2. In PD brains, GIGYF2 did not localise to Lewy bodies. Our findings indicate a role for GIGYF2 in the regulation of signalling at endosomes, but no contribution of GIGYF2 to the pathogenesis of PD.