Regulation of MEK/ERK pathway output by subcellular localization of B-Raf
Regulation of MEK/ERK pathway output by subcellular localization of B-Raf
复制标题
DOI：
10.1042/bst20110621
复制
发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Pritchard, Catrin
中科院分区：
文献类型：
--
作者：
Andreadi, Catherine;Noble, Catherine;Pritchard, Catrin
细胞内信号通路激活的强度和持续时间是细胞对细胞外信号反应的生物学结果的关键决定因素。这一点在Ras/Raf/MEK[丝裂原激活的生长因子/细胞外信号调节激酶]/ERK信号通路中被特别阐明，在成纤维细胞中的许多研究表明，持续的ERK信号是进入S期所必需的，而瞬时的ERK信号不具有这种能力。然而，一个主要的悬而未决的问题是，细胞如何维持ERK的激活，特别是当ERK特异的磷酸酶被信号转导途径本身转录上调时。ERK调控的一个要点是在Raf水平上，为了在ERK磷酸酶存在的情况下维持ERK的激活，持续的Raf激活是必需的。哺乳动物中存在三种大鼠蛋白，这三种蛋白的活性都是在生长因子刺激细胞后诱导的，但在以后的时间点只有B-大鼠的活性保持不变。这一观察结果表明，B-Raf是ERK持续激活的调节因子。在这篇综述中，我们考虑了B-大鼠和持续ERK激活之间存在联系的证据，重点是B-大鼠的亚细胞定位在这一关键生理事件中的潜在作用。
The strength and duration of intracellular signalling pathway activation is a key determinant of the biological outcome of cells in response to extracellular cues. This has been particularly elucidated for the Ras/Raf/MEK [mitogen-activated growth factor/ERK (extracellular-signal-regulated kinase) kinase]/ERK signalling pathway with a number of studies in fibroblasts showing that sustained ERK signalling is a requirement for S-phase entry, whereas transient ERK signalling does not have this capability. A major unanswered question, however, is how a cell can sustain ERK activation, particularly when ERK-specific phosphatases are transcriptionally up-regulated by the pathway itself. A major point of ERK regulation is at the level of Raf, and, to sustain ERK activation in the presence of ERK phosphatases, sustained Raf activation is a requirement. Three Rat proteins exist in mammals, and the activity of all three is induced following growth factor stimulation of cells, but only B-Rat activity is maintained at later time points. This observation points to B-Raf as a regulator of sustained ERK activation. In the present review, we consider evidence for a link between B-Rat and sustained ERK activation, focusing on a potential role for the subcellular localization of B-Rat in this key physiological event.