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
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
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DOI：
10.1210/me.2009-0011
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发表时间：
2009-07-01
影响因子：
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通讯作者：
Carter-Su, Christin
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文献类型：
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作者：
Maures, Travis J.;Chen, Linyi;Carter-Su, Christin
适配蛋白SH2B1 （SH2-B， PSM）被募集到多种配体激活的酪氨酸受体激酶，包括神经生长因子（NGF）、胰岛素和IGF-I的受体以及细胞因子受体相关的Janus激酶家族激酶。在本研究中，我们研究了SH2B1在NGF信号传导中的功能。我们发现使用短发夹RNA抑制SH2B1抑制内源性SH2B1抑制ngf依赖性神经突生长，但不抑制ngf介导的Akt或ERKs 1/2磷酸化。据推测，SH2B1定位于质膜并起作用。我们在SH2B1中发现了一个核定位信号，并表明这是SH2B1 β核易位所必需的。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，但可以阻止SH2B1 β增强ngf诱导的神经突生长。SH2B1 β核输入的中断也会阻止SH2B1 β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物受体和基质金属蛋白酶3和10的基因。通过核输出序列的突变破坏SH2B1 β核输出同样可以阻止SH2B1 β增强ngf诱导的这些基因的转录。高度同源的家族成员SH2B2（APS）未观察到核易位。综上所述，这些数据表明，SH2B1 β不仅仅是作为一种连接信号蛋白与质膜上活化的TrkA受体的适配器蛋白，它必须在质膜和细胞核之间穿梭，作为ngf诱导的基因表达和神经元分化的关键成分。（分子内分泌学23:1077-1091,2009）
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 SH2B1 beta. Mutation of the nuclear localization signal has no effect on NGF-induced activation of TrkA and ERKs 1/2 but prevents SH2B1 beta from enhancing NGF-induced neurite outgrowth. Disruption of SH2B1 beta nuclear import also prevents SH2B1 beta 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 SH2B1 beta nuclear export by mutation of its nuclear export sequence similarly prevents SH2B1 beta 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, SH2B1 beta must shuttle between the plasma membrane and nucleus to function as a critical component of NGF-induced gene expression and neuronal differentiation. (Molecular Endocrinology 23: 1077-1091, 2009)