Arrestin orchestrates crosstalk between G protein-coupled receptors to modulate the spatiotemporal activation of ERK MAPK.
Arrestin orchestrates crosstalk between G protein-coupled receptors to modulate the spatiotemporal activation of ERK MAPK.
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DOI：
10.1161/circresaha.109.198580
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发表时间：
2010-01-08
影响因子：
20.1
通讯作者：
Xiang Y
中科院分区：
文献类型：
--
作者：
Cervantes D;Crosby C;Xiang Y
G蛋白偶联受体(GPCRs)对多种细胞外刺激做出反应，调节细胞功能。尽管广泛的研究调查了单个gpr信号级联的调节，但伴随的gpr激活对下游信号和细胞功能的影响仍不清楚。我们的目标是描述GPCR串扰调节MAPK激活的细胞机制。通过操纵心脏成纤维细胞上的肾上腺素能受体，研究arrestin在ERK1/2 MAPK信号的时空调控中的作用。我们展示了一个一般的机制，其中arrestin被一个gpr激活，能够调节来自另一个gpr的信号。GQ偶联受体信号通路的激活导致ERK1/2 MAPK磷酸化时间延长、核积聚和细胞增殖。有趣的是，这些受体与β肾上腺素能受体(ARs)的共同激活诱导了位于胞浆中的瞬时ERK信号，从而抑制了细胞的增殖。进一步的研究表明，在β-2AR上募集阻滞素3可以通过直接将ERK与arrestin结合来协调GQ偶联受体诱导的ERK与胞浆的隔离。这是首次有证据表明，arrestin3充当协调者，整合来自多个GPCR的信号。我们的研究不仅提供了一种新的机制来解释不同GPCRs诱导的有丝分裂信号的整合，而且强调了GPCRs之间的信号串扰在体内的关键作用。
G protein-coupled receptors (GPCRs) respond to diversified extracellular stimuli to modulate cellular function. Despite extensive studies investigating the regulation of single GPCR signaling cascades, the effects of concomitant GPCR activation on downstream signaling and cellular function remain unclear. We aim to characterize the cellular mechanism by which GPCR cross-talk regulates MAPK activation. Adrenergic receptors on cardiac fibroblasts were manipulated to examine the role of arrestin in the spatiotemporal regulation of ERK1/2 MAPK signaling. We show a general mechanism in which arrestin activation by one GPCR is capable of regulating signaling originating from another GPCR. Activation of Gq-coupled receptor signaling leads to prolonged ERK1/2 MAPK phosphorylation, nuclear accumulation and cellular proliferation. Interestingly, co-activation of these receptors with the β adrenergic receptors (ARs) induced transient ERK signaling localized within the cytosol, which attenuated cell proliferation. Further studies revealed that recruitment of arrestin3 to the β2AR orchestrates the sequestration of Gq-coupled receptor-induced ERK to the cytosol through direct binding of ERK to arrestin. This is the first evidence showing that arrestin3 acts as a coordinator to integrate signals from multiple GPCRs. Our studies not only provide a novel mechanism explaining the integration of mitogenic signaling elicited by different GPCRs, but also underscore the critical role of signaling cross-talk among GPCRs in vivo.