Nerve growth factor/tropomyosin receptor kinase A (NGF/TrkA) signaling plays a key role in neuronal development, function, survival, and growth. The pathway is implicated in neurodegenerative disorders including Alzheimer’s disease, chronic pain, inflammation, and cancer. NGF binds the extracellular domain of TrkA, leading to the activation of the receptor’s intracellular kinase domain. As TrkA signaling is highly dynamic, mechanistic studies would benefit from a tool with high spatial and temporal resolution. Here we present the design and evaluation of four strategies for light-inducible activation of TrkA in the absence of NGF. Our strategies involve the light-sensitive protein Arabidopsis cryptochrome 2 and its binding partner CIB1. We demonstrate successful recapitulation of native NGF/TrkA functions by optical induction of plasma membrane recruitment and homo-interaction of the intracellular domain of TrkA. This approach activates PI3K/AKT and Raf/ERK signaling pathways, promotes neurite growth in PC12 cells, and supports survival of dorsal root ganglion neurons in the absence of NGF. This ability to activate TrkA using light bestows high spatial and temporal resolution for investigating NGF/TrkA signaling.

中文翻译：

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TrkA信号的光激活。

神经生长因子/原肌球蛋白受体激酶A（NGF / TrkA）信号传导在神经元发育，功能，存活和生长中起关键作用。该途径与神经退行性疾病有关，包括阿尔茨海默氏病，慢性疼痛，炎症和癌症。NGF结合TrkA的细胞外结构域，从而导致受体的细胞内激酶结构域激活。由于TrkA信号是高度动态的，因此机理研究将受益于具有高时空分辨率的工具。在这里，我们介绍了在缺乏NGF的情况下光诱导TrkA激活的四种策略的设计和评估。我们的策略涉及光敏感蛋白拟南芥cryptochrome 2及其绑定伙伴CIB1。我们通过光诱导质膜募集和TrkA胞内域的同质相互作用，证明了天然NGF / TrkA功能的成功概括。这种方法可以激活PI3K / AKT和Raf / ERK信号通路，促进PC12细胞中的神经突生长，并在缺乏NGF的情况下支持背根神经节神经元的存活。这种利用光激活TrkA的能力赋予了用于研究NGF / TrkA信号传导的高空间和时间分辨率。