Ataxin-2 modulates the levels of Grb2 and SRC but not ras signaling.
Ataxin-2 modulates the levels of Grb2 and SRC but not ras signaling.
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DOI：
10.1007/s12031-012-9949-4
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Auburger G
中科院分区：
文献类型：
--
作者：
Drost J;Nonis D;Eich F;Leske O;Damrath E;Brunt ER;Lastres-Becker I;Heumann R;Nowock J;Auburger G
Aaxin-2(ATXN_2)主要参与mRNA的加工。一些ATXN_2与受体酪氨酸激酶(RTK)结合，通过ATXN_2中的富含脯氨酸结构域(PRD)与Src中的SH3基序相互作用来抑制其内化。在脊髓小脑型共济失调2型(SCA2)和肌萎缩侧索硬化症(ALS)中，ATXN2功能的获得会导致神经元萎缩。相反，ATXN2基因敲除(KO)小鼠表现出肥大和胰岛素抵抗。为了阐明ATXN2对营养调控的影响，我们研究了ATXN2与众多蛋白质中SH3基序的相互作用，并观察到了一种新的与Grb2的相互作用。谷胱甘肽S转移酶下拉实验中的直接结合和内源蛋白的免疫共沉淀表明了一种生理上的关联。在SCA2患者成纤维细胞中，Grb2蛋白水平比Src蛋白水平更低，两种转录本的上调表明蛋白质周转能力增强。在KO小鼠胚胎成纤维细胞(MEF)中，Grb2和Src的蛋白水平降低。ATXN2的缺失本身不足以显著改变Grb2依赖的内源RAS水平、RAS-GTP水平、动力学和MEK1磷酸化信号，这表明其他因素补偿了增殖控制。在含有有丝分裂后神经元的KO组织中，Src蛋白水平显著降低，而不是Grb2。ATXN2突变调节RTK内吞复合体几个组分的水平，因此可能有助于改变细胞增殖以及翻译和生长。
Ataxin-2 (ATXN2) is implicated mainly in mRNA processing. Some ATXN2 associates with receptor tyrosine kinases (RTK), inhibiting their endocytic internalization through interaction of proline-rich domains (PRD) in ATXN2 with SH3 motifs in Src. Gain of function of ATXN2 leads to neuronal atrophy in the diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Conversely, ATXN2 knockout (KO) mice show hypertrophy and insulin resistance. To elucidate the influence of ATXN2 on trophic regulation, we surveyed interactions of ATXN2 with SH3 motifs from numerous proteins and observed a novel interaction with Grb2. Direct binding in glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation of the endogenous proteins indicated a physiologically relevant association. In SCA2 patient fibroblasts, Grb2 more than Src protein levels were diminished, with an upregulation of both transcripts suggesting enhanced protein turnover. In KO mouse embryonal fibroblasts (MEF), the protein levels of Grb2 and Src were decreased. ATXN2 absence by itself was insufficient to significantly change Grb2-dependent signaling for endogenous Ras levels, Ras-GTP levels, and kinetics as well as MEK1 phosphorylation, suggesting that other factors compensate for proliferation control. In KO tissue with postmitotic neurons, a significant decrease of Src protein levels is prominent rather than Grb2. ATXN2 mutations modulate the levels of several components of the RTK endocytosis complex and may thus contribute to alter cell proliferation as well as translation and growth.
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影响因子：
4.2
作者：
Chen, YongPing;Huang, Rui;Shang, Hui-Fang
通讯作者：
Shang, Hui-Fang
影响因子：
4.5
作者：
Al-Ramahi I;Pérez AM;Lim J;Zhang M;Sorensen R;de Haro M;Branco J;Pulst SM;Zoghbi HY;Botas J
通讯作者：
Botas J
影响因子：
12.4
作者：
Gross, I.;Armant, O.;Loeffler, J-P
通讯作者：
Loeffler, J-P
影响因子：
64.5
作者：
BUDAY, L;DOWNWARD, J
通讯作者：
DOWNWARD, J
影响因子：
--
作者：
Daoud, Hussein;Belzil, Veronique;Rouleau, Guy A.
通讯作者：
Rouleau, Guy A.