Sprouty2-mediated inhibition of fibroblast growth factor signaling is modulated by the protein kinase DYRK1A
Sprouty2-mediated inhibition of fibroblast growth factor signaling is modulated by the protein kinase DYRK1A
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DOI：
10.1128/mcb.00394-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
de la Luna, Susana
中科院分区：
文献类型：
--
作者：
Aranda, Sergi;Alvarez, Monica;de la Luna, Susana
由生长因子参与受体酪氨酸激酶（RTKs）启动的raf - mek细胞外信号调节激酶（Erk）信号通过一个复杂的正反馈和负反馈回路网络调节，这决定了细胞内信号的特异性和时空特征。众所周知的RTK信号拮抗剂是Sprouty蛋白。发芽蛋白的活性受磷酸化调节。然而，对这些翻译后修饰的激酶知之甚少。我们确定DYRK1A是Sprouty2的蛋白激酶之一。我们发现DYRK1A与Sprouty2相互作用并调节其磷酸化状态。此外，我们在体外和体内均发现Sprouty2上的Thr75是DYRK1A磷酸化位点。这个位点是功能性的，因为它的突变增强了Sprouty2对成纤维细胞生长因子（FGF）诱导的Erk信号的抑制功能。进一步支持功能相互作用的观点，DYRK1A和Sprouty2存在于小鼠大脑的蛋白质复合物中，它们的表达在几个结构中重叠。此外，这两种蛋白都与粗突触体制备的突触质膜组分共聚合，并在生长锥中共定位，这表明它们在神经末梢中起作用。因此，我们的研究结果表明，DYRK1A通过磷酸化依赖的Sprouty2抑制活性损伤，积极调节fgf -丝裂原激活的蛋白激酶信号。
Raf-MEK-extracellular signal-regulated kinase (Erk) signaling initiated by growth factor-engaged receptor tyrosine kinases (RTKs) is modulated by an intricate network of positive and negative feedback loops which determine the specificity and spatiotemporal characteristics of the intracellular signal. Well-known antagonists of RTK signaling are the Sprouty proteins. The activity of Sprouty proteins is modulated by phosphorylation. However, little is known about the kinases responsible for these posttranslational modifications. We identify DYRK1A as one of the protein kinases of Sprouty2. We show that DYRK1A interacts with and regulates the phosphorylation status of Sprouty2. Moreover, we identify Thr75 on Sprouty2 as a DYRK1A phosphorylation site in vitro and in vivo. This site is functional, since its mutation enhanced the repressive function of Sprouty2 on fibroblast growth factor (FGF)-induced Erk signaling. Further supporting the idea of a functional interaction, DYRK1A and Sprouty2 are present in protein complexes in mouse brain, where their expression overlaps in several structures. Moreover, both proteins copurify with the synaptic plasma membrane fraction of a crude synaptosomal preparation and colocalize in growth cones, pointing to a role in nerve terminals. Our results suggest, therefore, that DYRK1A positively regulates FGF-mitogen-activated protein kinase signaling by phosphorylation-dependent impairment of the inhibitory activity of Sprouty2.