The ERK cascade is a central signaling pathway that regulates a wide variety of cellular processes including proliferation, differentiation, learning and memory, development, and synaptic plasticity. A wide range of inputs travel from the membrane through different signaling pathway routes to reach activation of one set of output kinases, ERK1&2. The classical ERK activation pathway beings with growth factor activation of receptor tyrosine kinases. Numerous G-protein coupled receptors and ionotropic receptors also lead to ERK through increases in the second messengers calcium and cAMP. Though both types of pathways are present in diverse cell types, a key difference is that most stimuli to neurons, e.g. synaptic inputs, are transient, on the order of milliseconds to seconds, whereas many stimuli acting on non-neural tissue, e.g. growth factors, are longer duration. The ability to consolidate these inputs to regulate the activation of ERK in response to diverse signals raises the question of which factors influence the difference in ERK activation pathways. This review presents both experimental studies and computational models aimed at understanding the control of ERK activation and whether there are fundamental differences between neurons and other cells. Our main conclusion is that differences between cell types are quite subtle, often related to differences in expression pattern and quantity of some molecules such as Raf isoforms. In addition, the spatial location of ERK is critical, with regulation by scaffolding proteins producing differences due to colocalization of upstream molecules that may differ between neurons and other cells.

中文翻译：

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ERK激活之路：神经元是否采取替代途径？

ERK级联是调节多种细胞过程（包括增殖，分化，学习和记忆，发育和突触可塑性）的中央信号通路。各种各样的输入信号从膜通过不同的信号传导途径传播，从而激活一组输出激酶ERK1＆2。经典的ERK激活途径是受体酪氨酸激酶的生长因子激活。许多G蛋白偶联受体和离子受体也通过增加第二信使钙和cAMP导致ERK。尽管两种类型的途径都存在于不同的细胞类型中，但主要区别在于对神经元的大多数刺激（例如突触输入）是瞬态的，在毫秒到秒的数量级，而许多刺激作用于非神经组织，例如生长因子，持续时间更长。整合这些输入以调节ERK激活以响应各种信号的能力提出了一个问题，即哪些因素会影响ERK激活途径的差异。这篇综述介绍了旨在了解ERK激活控制以及神经元与其他细胞之间是否存在根本差异的实验研究和计算模型。我们的主要结论是，细胞类型之间的差异非常微妙，通常与某些分子（例如Raf亚型）的表达模式和数量差异有关。此外，ERK的空间位置非常关键，支架蛋白的调节会由于上游分子的共定位而产生差异，而上游分子的共定位可能会在神经元和其他细胞之间发生差异。整合这些输入以调节ERK激活以响应各种信号的能力提出了一个问题，即哪些因素会影响ERK激活途径的差异。这篇综述介绍了旨在了解ERK激活控制以及神经元与其他细胞之间是否存在根本差异的实验研究和计算模型。我们的主要结论是，细胞类型之间的差异非常微妙，通常与某些分子（例如Raf亚型）的表达模式和数量差异有关。此外，ERK的空间位置非常关键，支架蛋白的调节会由于上游分子的共定位而产生差异，而上游分子的共定位可能会在神经元和其他细胞之间发生差异。整合这些输入以调节ERK激活以响应各种信号的能力提出了一个问题，即哪些因素会影响ERK激活途径的差异。这篇综述介绍了旨在了解ERK激活控制以及神经元与其他细胞之间是否存在根本差异的实验研究和计算模型。我们的主要结论是，细胞类型之间的差异非常微妙，通常与某些分子（例如Raf亚型）的表达模式和数量差异有关。此外，ERK的空间位置非常关键，支架蛋白的调节会由于上游分子的共定位而产生差异，而上游分子的共定位可能会在神经元和其他细胞之间发生差异。