Isoform-specific optical activation of kinase function reveals p38-ERK signaling crosstalk.
Isoform-specific optical activation of kinase function reveals p38-ERK signaling crosstalk.
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DOI：
10.1039/d2cb00157h
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发表时间：
2023-10-04
影响因子：
4.1
通讯作者：
Deiters, Alexander
中科院分区：
文献类型：
--
作者：
Zhou, Wenyuan;Ryan, Amy;Janosko, Chasity P.;Shoger, Karsen E.;Haugh, Jason M.;Gottschalk, Rachel A.;Deiters, Alexander
进化通过产生源自相同基因的蛋白质同种型使哺乳动物蛋白质组多样化，例如，通过选择性基因剪接或翻译后修饰，或在基因家族中发现的非常相似的基因。蛋白质异构体可以具有重叠或独特的功能，并且传统的化学、生物化学和遗传技术由于其高度相似性而在区分异构体的能力方面常常受到限制。这在高度动态的细胞信号级联的背景下尤其如此，这通常需要急性时空扰动来评估机制细节。为此，我们描述了一种方法，用于选择性扰动的个别蛋白质亚型的丝裂原活化蛋白激酶（MAPK）p38。在保守的活性位点赖氨酸处的光笼化基团的遗传安装使得能够精确地光控制激酶信号传导的起始，随后调查下游事件。通过光学控制，我们已经确定了一个新的点串扰之间的两个主要的信号级联：p38/MAPK途径和细胞外信号调节激酶（ERK）/MAPK途径。具体地说，使用光活化的p38同种型，我们发现p38γ和p38δ变体是ERK信号级联的正调节剂，同时确认p38α和p38β变体是负调节剂。蛋白质同种型在细胞环境中难以区分。在这里，我们描述了急性光控制的个别亚型的丝裂原活化蛋白激酶（MAPK）p38，揭示了一个新的点之间的串扰两个MAPK途径。
Evolution has diversified the mammalian proteome by the generation of protein isoforms that originate from identical genes, e.g., through alternative gene splicing or post-translational modifications, or very similar genes found in gene families. Protein isoforms can have either overlapping or unique functions and traditional chemical, biochemical, and genetic techniques are often limited in their ability to differentiate between isoforms due to their high similarity. This is particularly true in the context of highly dynamic cell signaling cascades, which often require acute spatiotemporal perturbation to assess mechanistic details. To that end, we describe a method for the selective perturbation of the individual protein isoforms of the mitogen-activated protein kinase (MAPK) p38. The genetic installation of a photocaging group at a conserved active site lysine enables the precise light-controlled initiation of kinase signaling, followed by investigation of downstream events. Through optical control, we have identified a novel point of crosstalk between two major signaling cascades: the p38/MAPK pathway and the extracellular signal-regulated kinase (ERK)/MAPK pathway. Specifically, using the photoactivated p38 isoforms, we have found the p38γ and p38δ variants to be positive regulators of the ERK signaling cascade, while confirming the p38α and p38β variants as negative regulators. Protein isoforms are difficult to differentiate in a cellular context. Here, we describe the acute light control of individual isoforms of the mitogen-activated protein kinase (MAPK) p38, revealing a novel point of crosstalk between two MAPK pathways.
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