Convergence of signaling pathways on the activation of ERK in B cells
Convergence of signaling pathways on the activation of ERK in B cells
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DOI：
10.1074/jbc.m202485200
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发表时间：
2002-06-28
影响因子：
4.8
通讯作者：
Coggeshall, KM
中科院分区：
文献类型：
--
作者：
Jacob, A;Cooney, D;Coggeshall, KM
B细胞受体(BCR)启动了三个主要的信号通路：RAS通路，它导致细胞外信号调节激酶(ERR)的激活；磷脂酶C-伽马通路，引起钙动员；以及磷脂酰肌醇3-激酶(PI 3-K)通路。这些结合在一起，根据BCR信号的背景诱导不同的生物反应。Ras和PI3K通路对B细胞的发育和激活都是重要的。几个模型系统显示了这些途径之间存在交叉监管的证据。在这里，我们通过使用PI3K抑制剂和显性负的PI3K结构证明了BCR诱导的ERK的磷酸化和激活依赖于PI3K。PI-3-激酶在RAS的上游和下游多个点进入RAS信号级联。我们还表明ERK的激活依赖于磷脂酶C-γ，这与它对钙动员的依赖是一致的。最后，PI 3-激酶本身的激活完全依赖于RAS。我们的结论是，在B细胞中，PI-3-K和RAS信号级联关系密切，ERK的激活是一个信号整合点，因为它需要所有三个主要信号通路的同时输入。
The B cell receptor (BCR) initiates three major signaling pathways: the Ras pathway, which leads to extracellular signal-regulated kinase (ERR) activation; the phospholipase C-gamma pathway, which causes calcium mobilization; and the phosphoinositide 3-kinase (PI 3-kinase) pathway. These combine to induce different biological responses depending on the context of the BCR signal. Both the Ras and PI 3-kinase pathways are important for B cell development and activation. Several model systems show evidence of cross-regulation between these pathways. Here we demonstrate through the use of PI 3-kinase inhibitors and a dominant-negative PI 3-kinase construct that the BCR-induced phosphorylation and activation of ERK is dependent on PI 3-kinase. PI 3-kinase feeds into the Ras signaling cascade at multiple points, both upstream and downstream of Ras. We also show that ERK activation is dependent on phospholipase C-gamma, in keeping with its dependence on calcium mobilization. Last, the activation of PI 3-kinase itself is completely dependent on Ras. We conclude that the PI 3-kinase and Ras signaling cascades are intimately connected in B cells and that the activation of ERK is a signal integration point, since it requires simultaneous input from all three major signaling pathways.