Tyrosine phosphatase SHP-2 is a regulator of p27Kip1 tyrosine phosphorylation
Tyrosine phosphatase SHP-2 is a regulator of p27Kip1 tyrosine phosphorylation
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DOI：
10.4161/cc.7.24.7260
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发表时间：
2008-12
期刊：
影响因子：
4.3
通讯作者：
Irini Tossidou;M. Dangers;A. Koch;Dominique T Brandt;M. Schiffer;C. Kardinal
中科院分区：
文献类型：
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作者：
Irini Tossidou;M. Dangers;A. Koch;Dominique T Brandt;M. Schiffer;C. Kardinal
细胞周期调节因子p27 Kip 1的酪氨酸磷酸化在其与细胞周期蛋白依赖性激酶的结合及其亚细胞定位中起着至关重要的作用。虽然Src和Bcr-Abl被证明是负责酪氨酸磷酸化，没有数据可用于p27 Kip 1和磷酸酶参与的去磷酸化。考虑到相关的去磷酸化是细胞周期蛋白调控中的关键事件，我们将重点放在酪氨酸磷酸酶SHP-2上，该磷酸酶在G-CSF刺激下在早幼粒细胞白血病细胞中受到调控。因此，我们发现SHP-2与p27 Kip 1和G-CSF受体相关，并且我们观察到SHP-2在G-CSF刺激下发生核转位。使用SHP-2的催化失活形式和针对SHP-2的siRNA，我们可以证明SHP-2参与p27 Kip 1的酪氨酸去磷酸化。此外，SHP-2强烈激活G-CSF刺激和特异性去磷酸化p27 Kip 1在体外。最重要的是，我们可以说明SHP-2调节p27 Kip 1的稳定性，并有助于p27 Kip 1介导的细胞周期进程。综上所述，我们的研究结果表明，SHP-2是p27 Kip 1酪氨酸磷酸化的关键调节因子。
Tyrosine phosphorylation of the cell cycle regulator p27Kip1 plays a crucial role in its binding to cyclin dependent kinases and its subcellular localization. While Src and Bcr-Abl were shown to be responsible for tyrosine phosphorylation, no data are available on the dephosphorylation of p27Kip1 and the phosphatase involved. Considering the associated dephosphorylation as a pivotal event in the regulation of cell cycle proteins, we focused on the tyrosine phosphatase SHP-2, which is regulated in promyelocytic leukemia cells on G-CSF stimulation. SHP-2 was thus found in association with p27Kip1 and the G-CSF receptor, and we observed a nuclear translocation of SHP-2 on G-CSF stimulation. Using a catalytically inactive form of SHP-2 and siRNA directed against SHP-2, we could demonstrate the involvement of SHP-2 in tyrosine dephosphorylation of p27Kip1. Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27Kip1 in vitro. Most importantly, we could illustrate that SHP-2 modulates p27Kip1 stability and contributes to p27Kip1-mediated cell cycle progression. Taken together, our results demonstrate that SHP-2 is a key regulator of p27Kip1 tyrosine phosphorylation.