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首页> 外文期刊>Oncogene >Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-dependent, but not nerve growth factor-independent, differentiation and cell cycle arrest in the human neuroblastoma cell line, SY5Y
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Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-dependent, but not nerve growth factor-independent, differentiation and cell cycle arrest in the human neuroblastoma cell line, SY5Y

机译：TrkA中活化环酪氨酸的酸性取代支持人神经母细胞瘤细胞SY5Y中神经生长因子依赖性而不是神经生长因子依赖性分化和细胞周期停滞

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TrkA is the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and stimulates NGF-dependent cell survival and differentiation in primary neurons and also differentiation of neuroblastomas and apoptosis of medulloblastomas. We have previously shown that aspartic acid and glutamic acid substitution (AspGlu and GluAsp) of the activation loop tyrosines in TrkA (Tyr683 and Tyr684) supports NGF-independent neuritogenesis and cell survival in PC12 cell-derived nnr5 cells. In this study, the AspGlu and GluAsp mutant Trks have been analysed for their ability to support NGF-independent and NGF-dependent neuritogenesis, proliferation and cell signalling in the human neuroblastoma cell line, SY5Y. We find that the AspGlu and GluAsp mutant Trks support NGF-dependent, but not NGF-independent, autophosphorylation, neuritogenic responses and/or inhibit cell cycle progression. The NGF-dependent neuritogenic responses are lower for the mutant Trks (approximately 30–60% for AspGlu and 50–60% for GluAsp), relative to wild-type TrkA. While both the AspGlu and GluAsp mutant Trks support NGF-dependent transient phosphorylation of Shc, PLC-1, AKT, FRS2, SH2B as well as prolonged MAP kinase activation, the GluAsp mutant induces stronger NGF-dependent tyrosine phosphorylation of FRS2 and SH2B, as well as a stronger reduction in bromodeoxyuridine (BrdU) incorporation. Collectively, these data suggest that neither absolute levels of receptor autophosphorylation, high levels of TrkA expression nor the activation of a specific signalling pathway is dominant and absolutely essential for neuritogenesis and cell cycle arrest of SY5Y cells.
机译：TrkA是神经生长因子（NGF）的受体酪氨酸激酶（RTK），可刺激NGF依赖性细胞在原代神经元中的存活和分化，以及神经母细胞瘤的分化和髓母细胞瘤的凋亡。我们以前已经表明，在TrkA（Tyr683和Tyr684）中激活环酪氨酸的天冬氨酸和谷氨酸取代（AspGlu和GluAsp）支持NGF依赖性神经形成和PC12细胞来源的nnr5细胞的细胞存活。在这项研究中，已经分析了AspGlu和GluAsp突变型Trks在人成神经细胞瘤细胞系SY5Y中支持NGF依赖性和NGF依赖性神经形成，增殖和细胞信号转导的能力。我们发现AspGlu和GluAsp突变体Trks支持NGF依赖性，但不是NGF依赖性，自身磷酸化，中性神经反应和/或抑制细胞周期进程。相对于野生型TrkA，突变型Trks的NGF依赖性神经生成反应较低（AspGlu约为30-60％，GluAsp约为50-60％）。虽然AspGlu和GluAsp突变体Trks均支持Shc，PLC-1，AKT，FRS2，SH2B的NGF依赖性瞬时磷酸化以及延长的MAP激酶激活，但GluAsp突变体诱导FRS2和SH2B的NGF依赖性酪氨酸磷酸化更强，如以及降低溴脱氧尿苷（BrdU）的掺入量。总体而言，这些数据表明，对于SY5Y细胞的神经形成和细胞周期阻滞，绝对的受体自身磷酸化水平，高水平的TrkA表达或特定信号通路的激活都不是主要的，也绝对不是必需的。

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