The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complex
The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complex
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DOI：
10.1073/pnas.190276697
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发表时间：
2000-09-26
影响因子：
11.1
通讯作者：
Bunnett, NW
中科院分区：
文献类型：
--
作者：
DeFea, KA;Vaughn, ZD;Bunnett, NW
最近有人提出，在细胞外信号调节激酶1和2(ERK1/2)的激活和亚细胞定位中，需要含有内化的G蛋白偶联受体和β-拦阻素的支架复合体。然而，这些复合体的组成以及这一要求对ERK1/2功能的重要性似乎在不同的受体之间是不同的。本文报道了P物质(SP)激活神经激肽-1受体(NK1R)刺激由内化受体β-arrestin、src组成的支架复合体的形成。和ERK1/2(通过凝胶过滤、免疫沉淀和免疫荧光检测)。通过表达显性阴性的β-arrestin或不与β-arrestin相互作用的截短的NK1R来抑制复合体的形成。抑制SP刺激的NK1R的内吞作用和ERK1/2的激活，而ERK1/2是SP的增殖和抗凋亡作用所必需的。因此，含有β-arrestin的复合体的形成有助于SP的增殖和抗凋亡作用，并且在表达与自然发生的变体相对应的截短NK1R的细胞中，SP的这些作用可以减弱。
A requirement for scaffolding complexes containing internalized G protein-coupled receptors and beta-arrestins in the activation and subcellular localization of extracellular signal-regulated kinases 1 and 2 (ERK1/2) has recently been proposed. However, the composition of these complexes and the importance of this requirement for function of ERK1/2 appear to differ between receptors. Here we report that substance P (SP) activation of neurokinin-1 receptor (NK1R) stimulates the formation of a scaffolding complex comprising internalized receptor, beta-arrestin, src. and ERK1/2 (detected by gel filtration, immunoprecipitation, and immunofluorescence). Inhibition of complex formation, by expression of dominant-negative beta-arrestin or a truncated NK1R that fails to interact with beta-arrestin. inhibits both SP-stimulated endocytosis of the NK1R and activation of ERK1/2 which is required for the proliferative and antiapoptotic effects of SP. Thus, formation of a beta-arrestin-containing complex facilitates the proliferative and antiapoptotic effects of SP, and these effects of SP could be diminished in cells expressing truncated NK1R corresponding to a naturally occurring variant.