PBX1 nuclear export is regulated independently of PBX-MEINOX interaction by PKA phosphorylation of the PBC-B domain
PBX1 nuclear export is regulated independently of PBX-MEINOX interaction by PKA phosphorylation of the PBC-B domain
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DOI：
10.1093/emboj/cdg010
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发表时间：
2003-01-02
期刊：
影响因子：
11.4
通讯作者：
Zappavigna, V
中科院分区：
文献类型：
--
作者：
Kilstrup-Nielsen, C;Alessio, M;Zappavigna, V
通过亚细胞分布调节PBC蛋白的功能是附件图案化的一个重要的进化保守机制。我们调查了控制Pbx1核出口的过程。在这里，我们表明，在没有MEINOX蛋白的情况下，核输出不是Pbx1亚细胞定位的默认途径。在不同的细胞背景下，Pbx1可以从细胞核输入或输出，而不依赖于它与MEINOX蛋白的相互作用。Pbx1的核输出和输入之间的细胞上下文特定的平衡由PBC-B结构域控制，该结构域包含几个保守的丝氨酸残基，对应于Ser/Thr激酶的磷酸化位点。PBX1的亚细胞定位与这些残基的磷酸化状态有关，这些残基的去磷酸化导致核输出。蛋白激酶A(PKA)在这些丝氨酸上特异性地磷酸化Pbx1，体内内源性PKA活性的刺激阻止了Pbx1在远端肢体间充质细胞中的核输出。我们的结果揭示了除了缺乏MEINOX蛋白外，控制Pbx1核输出的一种新机制，包括抑制PBC-B结构域中特定位置的PKA介导的磷酸化。
The regulation of PBC protein function through subcellular distribution is a crucial evolutionarily conserved mechanism for appendage patterning. We investigated the processes controlling PBX1 nuclear export. Here we show that in the absence of MEINOX proteins nuclear export is not a default pathway for PBX1 subcellular localization. In different cell backgrounds, PBX1 can be imported or exported from the nucleus independently of its capacity to interact with MEINOX proteins. The cell context-specific balance between nuclear export and import of PBX1 is controlled by the PBC-B domain, which contains several conserved serine residues corresponding to phosphorylation sites for Ser/Thr kinases. PBX1 subcellular localization correlates with the phosphorylation state of these residues whose dephosphorylation induces nuclear export. Protein kinase A (PKA) specifically phosphorylates PBX1 at these serines, and stimulation of endogenous PKA activity in vivo blocks PBX1 nuclear export in distal limb mesenchymal cells. Our results reveal a novel mechanism for the control of PBX1 nuclear export in addition to the absence of MEINOX protein, which involves the inhibition of PKA-mediated phosphorylation at specific sites within the PBC-B domain.