Arrestin-mediated signaling: Is there a controversy?
Arrestin-mediated signaling: Is there a controversy?
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DOI：
10.4331/wjbc.v9.i3.25
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发表时间：
2018-12-12
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影响因子：
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通讯作者：
Gurevich, Eugenia V
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作者：
Gurevich, Vsevolod V;Gurevich, Eugenia V
有丝分裂原激活蛋白(MAP)激酶细胞外信号调节激酶(ERK)1/2的激活传统上被用来作为G蛋白偶联受体(GPCRs)信号的读数，而不是通过G蛋白来读出信号。最近利用HEK293细胞进行的几项研究表明，ERK1/2的磷酸化需要G蛋白的活性，但不一定需要非视觉抑制蛋白的存在。这似乎与主流范式相矛盾。在这里，我们讨论这些结果以及关于基因编辑细胞和arrestin介导的信号转导的最新数据。我们认为没有真正的争议。G蛋白可能参与了最上游的MAP3K的激活，尽管在体内大多数MAP3K的激活不依赖于异源三聚体G蛋白，是由受体酪氨酸激酶和/或整合素启动的。就MAP激酶而言，阻滞素最确定的作用是作为三层级联(MAP3K-MAP2K-MAPK)的支架。因此，拦阻蛋白可能是GPCR结合的和游离的，促进了信号在这些级联中的传播，而通过MAP3K激活的信号启动可能不依赖于拦阻蛋白。不同的MAP3K被不同的输入激活，其中一些是由G蛋白介导的，特别是在细胞培养中，我们人为地阻止了受体酪氨酸激酶和整合素的信号传递，从而有利于GPCR诱导的信号传递。因此，没有理由改变这一范式：拦阻蛋白和G蛋白在细胞信号传递中扮演着截然不同的非重叠角色。
The activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK)1/2 was traditionally used as a readout of signaling of G protein-coupled receptors (GPCRs) via arrestins, as opposed to conventional GPCR signaling via G proteins. Several recent studies using HEK293 cells where all G proteins were genetically ablated or inactivated, or both non-visual arrestins were knocked out, demonstrated that ERK1/2 phosphorylation requires G protein activity, but does not necessarily require the presence of non-visual arrestins. This appears to contradict the prevailing paradigm. Here we discuss these results along with the recent data on gene edited cells and arrestin-mediated signaling. We suggest that there is no real controversy. G proteins might be involved in the activation of the upstream-most MAP3Ks, although in vivo most MAP3K activation is independent of heterotrimeric G proteins, being initiated by receptor tyrosine kinases and/or integrins. As far as MAP kinases are concerned, the best-established role of arrestins is scaffolding of the three-tiered cascades (MAP3K-MAP2K-MAPK). Thus, it seems likely that arrestins, GPCR-bound and free, facilitate the propagation of signals in these cascades, whereas signal initiation via MAP3K activation may be independent of arrestins. Different MAP3Ks are activated by various inputs, some of which are mediated by G proteins, particularly in cell culture, where we artificially prevent signaling by receptor tyrosine kinases and integrins, thereby favoring GPCR-induced signaling. Thus, there is no reason to change the paradigm: Arrestins and G proteins play distinct non-overlapping roles in cell signaling.