Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation
Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation
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DOI：
10.1074/jbc.m003259200
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发表时间：
2000-07-21
影响因子：
4.8
通讯作者：
Baccarini, M
中科院分区：
文献类型：
--
作者：
Abraham, D;Podar, K;Baccarini, M
Raf-1激酶在传递由有丝分裂原或癌基因诱导的增殖信号中起着关键作用，Raf-1受到复杂而不完全了解的机制的调节，包括磷酸化。许多研究表明，丝氨酸259和621的磷酸化可以抑制Raf-1激酶，我们发现这两种丝氨酸在早期有丝分裂刺激时都是低磷酸化的，并且低磷酸化与Raf-1的激活峰值相关。选择性抑制蛋白磷酸酶2A(PP2A)的冈田酸浓度可诱导这些残基的磷酸化，并阻止Raf-1激酶的最大激活。这种作用是通过丝氨酸259的磷酸化来实现的。PP2A核心异源二聚体与Raf-1在体内和体外形成复合体。这些数据证实PP2A是Raf-1激活的正向调节因子，并首次表明PP2A可能支持相关激酶的激活。
The Raf-1 kinase plays a key role in relaying proliferation signals elicited by mitogens or oncogenes, Raf-1 is regulated by complex and incompletely understood mechanisms including phosphorylation, A number of studies have indicated that phosphorylation of serines 259 and 621 can inhibit the Raf-1 kinase, We show that both serines are hypophosphorylated during early mitogenic stimulation and that hypophosphorylation correlates with peak Raf-1 activation. Concentrations of okadaic acid that selectively inhibit protein phosphatase 2A (PP2A) induce phosphorylation of these residues and prevent maximal activation of the Raf-1 kinase. This effect is mediated via phosphorylation of serine 259. The PP2A core heterodimer forms complexes with Raf-1 in vivo and in vitro. These data identify PP2A as a positive regulator of Raf-1 activation and are the first indication that PP2A may support the activation of an associated kinase.