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首页> 外文期刊>Molecular and Cellular Biology >APPL1 Associates with TrkA and GIPC1 and Is Required for Nerve Growth Factor-Mediated Signal Transduction
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APPL1 Associates with TrkA and GIPC1 and Is Required for Nerve Growth Factor-Mediated Signal Transduction

机译：APPL1与TrkA和GIPC1相关联，并且是神经生长因子介导的信号转导所必需的

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The neurotrophin receptor TrkA plays critical roles in the nervous system by recruiting signaling molecules that activate pathways required for the growth and survival of neurons. Here, we report APPL1 as a TrkA-associated protein. APPL1 and TrkA coimmunoprecipitated in sympathetic neurons. We have identified two routes through which this association can occur. APPL1 was isolated as a binding partner for the TrkA-interacting protein GIPC1 from rat brain lysate by mass spectrometry. The PDZ domain of GIPC1 directly engaged the C-terminal sequence of APPL1. This interaction provides a means through which APPL1 may be recruited to TrkA. In addition, the APPL1 PTB domain bound to TrkA, indicating that APPL1 may associate with TrkA independently of GIPC1. Isolation of endosomal fractions by high-resolution centrifugation determined that APPL1, GIPC1, and phosphorylated TrkA are enriched in the same fractions. Reduction of APPL1 or GIPC1 protein levels suppressed nerve growth factor (NGF)-dependent MEK, extracellular signal-regulated kinase, and Akt activation and neurite outgrowth in PC12 cells. Together, these results indicate that GIPC1 and APPL1 play a role in TrkA function and suggest that a population of endosomes bearing a complex of APPL1, GIPC1, and activated TrkA may transmit NGF signals.
机译：神经营养蛋白受体TrkA通过募集激活神经元生长和存活所需途径的信号传导分子，在神经系统中发挥关键作用。在这里，我们报告APPL1作为TrkA相关蛋白。 APPL1和TrkA在交感神经元中共免疫沉淀。我们已经确定了发生这种关联的两条途径。通过质谱从大鼠脑裂解物中分离出APPL1作为与TrkA相互作用蛋白GIPC1的结合伴侣。 GIPC1的PDZ结构域直接与APPL1的C端序列结合。这种相互作用提供了一种方法，通过该方法可以将APPL1募集到TrkA。此外，APPL1 PTB域绑定到TrkA，表明APPL1可以独立于GIPC1与TrkA关联。通过高分辨率离心分离内体组分，可确定APPL1，GIPC1和磷酸化的TrkA富含相同组分。 APPL1或GIPC1蛋白水平的降低抑制了PC12细胞中神经生长因子（NGF）依赖的MEK，细胞外信号调节激酶以及Akt激活和神经突的生长。总之，这些结果表明GIPC1和APPL1在TrkA功能中发挥作用，并表明带有APPL1，GIPC1和活化的TrkA的复合体的内体群体可能会传递NGF信号。

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