神经生长因子（NGF）依赖性神经突生长和NGF响应基因子集表达的增强需要衔接蛋白SH2B1β（SH2-Bβ）的胞质穿梭。,Molecular Endocrinology

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神经生长因子（NGF）依赖性神经突生长和NGF响应基因子集表达的增强需要衔接蛋白SH2B1β（SH2-Bβ）的胞质穿梭。
Molecular Endocrinology Pub Date : 2009-07-01 , DOI: 10.1210/me.2009-0011
Travis J. Maures , Linyi Chen , Christin Carter-Su

衔接蛋白SH2B1（SH2-B，PSM）被募集到多种配体激活的受体酪氨酸激酶，包括神经生长因子（NGF），胰岛素和IGF-1的受体以及与细胞因子受体相关的Janus激酶家族激酶。在这项研究中，我们检查了SH2B1在NGF信号传导中的功能。我们显示，使用短发夹RNA对抗SH2B1消耗内源性SH2B1可以抑制NGF依赖的神经突向外生长，但不能抑制NGF介导的Akt或ERKs 1/2的磷酸化。已经假设SH2B1定位于质膜并在质膜上起作用。我们确定SH2B1内的核定位信号，并表明它是SH2B1beta核转位所必需的。核定位信号的突变对NGF诱导的TrkA和ERKs 1/2的激活没有影响，但阻止SH2B1beta增强NGF诱导的神经突生长。SH2B1beta核输入的破坏也阻止SH2B1beta增强NGF诱导的神经元分化重要基因的转录，包括编码尿激酶纤溶酶原激活剂受体的基因以及基质金属蛋白酶3和10。SH2B1beta核输出因其核输出序列的突变而破坏也同样防止了转录。 SH2B1beta增强NGF诱导的那些基因的转录。没有观察到高度同源的家族成员SH2B2（APS）的核易位。总之，这些数据表明，不仅仅是将衔接蛋白与质膜上活化的TrkA受体连接的衔接蛋白，

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Nucleocytoplasmic Shuttling of the Adapter Protein SH2B1β (SH2-Bβ) Is Required for Nerve Growth Factor (NGF)-Dependent Neurite Outgrowth and Enhancement of Expression of a Subset of NGF-Responsive Genes

The adapter protein SH2B1 (SH2-B, PSM) is recruited to multiple ligand-activated receptor tyrosine kinases, including the receptors for nerve growth factor (NGF), insulin, and IGF-I as well as the cytokine receptor-associated Janus kinase family kinases. In this study, we examine SH2B1's function in NGF signaling. We show that depleting endogenous SH2B1 using short hairpin RNA against SH2B1 inhibits NGF-dependent neurite outgrowth, but not NGF-mediated phosphorylation of Akt or ERKs 1/2. SH2B1 has been hypothesized to localize and function at the plasma membrane. We identify a nuclear localization signal within SH2B1 and show that it is required for nuclear translocation of SH2B1beta. Mutation of the nuclear localization signal has no effect on NGF-induced activation of TrkA and ERKs 1/2 but prevents SH2B1beta from enhancing NGF-induced neurite outgrowth. Disruption of SH2B1beta nuclear import also prevents SH2B1beta from enhancing NGF-induced transcription of genes important for neuronal differentiation, including those encoding urokinase plasminogen activator receptor, and matrix metalloproteinases 3 and 10. Disruption of SH2B1beta nuclear export by mutation of its nuclear export sequence similarly prevents SH2B1beta enhancement of NGF-induced transcription of those genes. Nuclear translocation of the highly homologous family member SH2B2(APS) was not observed. Together, these data suggest that rather than simply acting as an adapter protein linking signaling proteins to the activated TrkA receptor at the plasma membrane, SH2B1beta must shuttle between the plasma membrane and nucleus to function as a critical component of NGF-induced gene expression and neuronal differentiation.

更新日期：2009-07-01

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