The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling
The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling
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DOI：
10.1016/j.cellsig.2006.05.020
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发表时间：
2007-01-01
影响因子：
4.8
通讯作者：
Bouvier, Michel
中科院分区：
文献类型：
--
作者：
Charest, Pascale G.;Oligny-Longpre, Genevieve;Bouvier, Michel
V2加压素受体(V2R)通过与支架蛋白βarrestin相关的机制激活丝裂原激活蛋白激酶(MAPK)ERK1/2。本文报道这种激活途径不依赖于GαS、GαI、GαQ或Gβα，并且V2R介导的GαS的激活以cAMP/PKA依赖的方式抑制ERKI/2的活性。在所研究的HEK293细胞中，研究发现，β-arrestin促进的激活超过了PKA介导的抑制该通路，导致了血管加压素刺激的ERK1/2的强烈激活。尽管有很强的MAPK活性，但与其他GPCR相比，V2R并未诱导DNA合成显著增加，这与V2R与βarrestin之间的稳定相互作用阻止了信号向细胞核传播的观点一致。研究发现，β-arrestin对于ERK1/2的激活是必不可少的，这表明在没有任何其他刺激信号的情况下，支架蛋白的募集是必要的，并且足以启动信号。基于选择性药物抑制剂、显性负性突变体和siRNA的使用，我们得出结论：V2R对Erki/2的依赖于β-arrestin的激活涉及c-Src和依赖于金属蛋白酶的反式激活事件。这些发现表明，β-arrestin是一种真正的信号起始剂，它可以在天然配体刺激GPCR时，单独启动MAPK的激活机制。(C)2006 Elsevier Inc.保留所有权利。
The V2 vasopressin receptor (V2R) activates the mitogen activated protein kinases (MAPK) ERK 1/2 through a mechanism involving the scaffolding protein beta arrestin. Here we report that this activating pathway is independent of G alpha s, G alpha i, G alpha q or G beta alpha and that the V2R-mediated activation of G alpha s inhibits ERKI/2 activity in a cAMP/PKA-dependent manner. In the HEK293 cells studied, the beta arrestin-promoted activation was found to dominate over the PKA-mediated inhibition of the pathway, leading to a strong vasopressin-stimulated ERK1/2 activation. Despite the strong MAPK activation and in contrast with other GPCR, V2R did not induce any significant increase in DNA synthesis, consistent with the notion that the stable interaction between V2R and beta arrestin prevents signal propagation to the nucleus. beta arrestin was found to be essential for the ERK1/2 activation, indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues. Based on the use of selective pharmacological inhibitors, dominant negative mutants and siRNA, we conclude that the beta arrestin-dependent activation of ERKI/2 by the V2R involves c-Src and a metalloprotemase-dependent trans-activation event. These findings demonstrate that beta arrestin is a genuine signalling initiator\that can, on its own, engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand. (c) 2006 Elsevier Inc. All rights reserved.