Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.     

黄三角装备制造业区域产业专业化发展的实证分析

结合区位商分析法、数据包络分析法以及市场占有率指标法对2015年黄三角装备制造业七大行业的产业专业化程度、产业效率以及市场绩效等方面进行实证分析。结果表明:黄三角装备制造业的总体发展状况良好,七大行业的区域特征明显。针对部分城市出现的规模报酬递减以及市场占有率下滑现象,按照区域分工、优势互补、弱势协作等思路提出发展策略以实现区域经济的全面发展。     

Global view of Hopf bifurcations of a van der Pol oscillator with delayed state feedback

This paper presents both analytical and numerical studies on the global view of Hopf bifurcations of a van der Pol oscillator with delayed state feedback. Based on a detailed analysis of the stability switches of the trivial equilibrium of the system, the stability charts are given in a parameter space consisting of the time delay and the feedback gains. The center manifold reduction and the normal form method are used to study Hopf bifurcations with respect to the time delay. To gain an insight into the pe...     

核桃青皮主要活性物质及提取工艺研究进展

核桃青皮中含有多种活性物质,具有抑菌、杀虫、抗病毒等多种功效,然而其成分含量、提取工艺、检测技术存在差异。本文归纳整理了国内外与青皮主要活性物质的相关文献,综述其主要的有效成分、提取工艺、检测技术,为优化核桃青皮主要有效成分的提取工艺、进一步开发核桃青皮资源高效利用提供科学依据。     

钢轨闪光对焊温度场分布的有限元分析

为研究钢轨闪光对焊闪光阶段的温度场分布,建立了三维实体有限元模型.计算过程中考虑了温度对材料相变和热物理特性的影响,运用"生死"单元技术解决闪光时液体过梁爆破引起物质烧损的模拟问题,同时采用红外电视图像测温法实时测量闪光阶段温度场分布.结果表明,有限元分析结果与实验结果十分吻合,为选择和优化闪光焊焊接参数提供了重要的手段,为后续闪光焊过程顶锻阶段热力耦合过程的模拟奠定了基础.     

钛合金磨削加工研究的进展

对国内外在钛合金磨削方面的研究现状进行了概述,分析了国内在此研究领域的发展方向,指出待解决的主要问题.对钛合金磨削加工的进一步研究很有参考价值.