Growth factor-induced p42/p44 MAPK nuclear translocation and retention requires both MAPK activation and neosynthesis of nuclear anchoring proteins.
Growth factor-induced p42/p44 MAPK nuclear translocation and retention requires both MAPK activation and neosynthesis of nuclear anchoring proteins.
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DOI：
10.1083/jcb.142.3.625
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发表时间：
1998-08-10
期刊：
影响因子：
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通讯作者：
Pouysségur J
中科院分区：
文献类型：
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作者：
Lenormand P;Brondello JM;Brunet A;Pouysségur J
丝裂原活化蛋白激酶（p42/p44 MAPK，也称为Erk 2和Erk 1）是从细胞表面到细胞核的信号转导的关键介质。我们以前已经表明，p42/p44 MAPK的激活所需的有丝分裂信号转导与这些激酶的快速核转位。然而，p42和p44 MAPK在胞质活化后易位到细胞核中的方式仍然不清楚，并且不能简单地从它们的蛋白质序列推断。在这项研究中，我们已经证明，激活p42/ p44 MAPK途径是必要的，足以触发p42和p44 MAPK的核转位。首先，加入MEK抑制剂PD 98059，阻断p42/p44 MAPK通路的激活，阻止核积累，而嵌合体ΔRaf-1：ER直接激活p42/p44 MAPK通路足以促进p42/p44 MAPK的核积累。此外，我们已经表明，这种核积累的p42/p44 MAPK需要新合成的短寿命的蛋白质。事实上，蛋白质合成抑制剂消除细胞核的积累，在血清和加速p42/p44 MAPK的持续激活的条件下，p42/p44 MAPK的核外排。相反，蛋白酶体抑制靶向蛋白水解协同增强p42/p44 MAPK核定位的非促有丝分裂激动剂和显着延长核定位的p42/p44 MAPK促有丝分裂刺激后。因此，我们得出结论，MAPK核转位需要激活的p42/p44 MAPK模块和新合成的短寿命的蛋白质，我们假设是核锚。
Mitogen-activated protein kinases (p42/p44 MAPK, also called Erk2 and Erk1) are key mediators of signal transduction from the cell surface to the nucleus. We have previously shown that the activation of p42/p44 MAPK required for transduction of mitogenic signaling is associated with a rapid nuclear translocation of these kinases. However, the means by which p42 and p44 MAPK translocate into the nucleus after cytoplasmic activation is still not understood and cannot simply be deduced from their protein sequences. In this study, we have demonstrated that activation of the p42/ p44 MAPK pathway was necessary and sufficient for triggering nuclear translocation of p42 and p44 MAPK. First, addition of the MEK inhibitor PD 98059, which blocks activation of the p42/p44 MAPK pathway, impedes the nuclear accumulation, whereas direct activation of the p42/p44 MAPK pathway by the chimera ΔRaf-1:ER is sufficient to promote nuclear accumulation of p42/p44 MAPK. In addition, we have shown that this nuclear accumulation of p42/p44 MAPK required the neosynthesis of short-lived proteins. Indeed, inhibitors of protein synthesis abrogate nuclear accumulation in response to serum and accelerate p42/p44 MAPK nuclear efflux under conditions of persistent p42/p44 MAPK activation. In contrast, inhibition of targeted proteolysis by the proteasome synergistically potentiated p42/p44 MAPK nuclear localization by nonmitogenic agonists and markedly prolonged nuclear localization of p42/p44 MAPK after mitogenic stimulation. We therefore conclude that the MAPK nuclear translocation requires both activation of the p42/p44 MAPK module and neosynthesis of short-lived proteins that we postulate to be nuclear anchors.