DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5
DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5
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DOI：
10.1016/j.cellsig.2007.12.014
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发表时间：
2008-05-01
影响因子：
4.8
通讯作者：
Cook, Simon J.
中科院分区：
文献类型：
--
作者：
Arkell, Rebecca S.;Dickinson, Robin J.;Cook, Simon J.
细胞外信号调节激酶-1和-2 （ERK1/2）可通过TEY基序的双苏氨酸和酪氨酸磷酸化激活。高度相关的激酶ERK5也可通过TEY基序的磷酸化激活。ERK1/2的失活是由双特异性蛋白磷酸酶（DUSP）家族的不同成员实现的，这些成员负责TEY基序的特异性、受调节的去磷酸化。这些酶包括核酶（DUSP5）和细胞质酶（DUSP6）。DUSP6是一种候选肿瘤抑制基因，被认为对ERK1/2的失活具有高度特异性，但一些报道表明它也可能使ERK5失活。这里我们比较了DUSP6调节ERK1/2和ERK5蛋白激酶的能力。我们发现DUSP6在酵母和人类细胞中都能与ERK1/2结合，但不能与ERK5结合。重组ERK2可以诱导DUSP6的催化活化，而ERK5则不能。异位表达的DUSP6可以使共表达的ERK2结构去磷酸化，但不会使ERK5去磷酸化。最后，DUSP6的表达阻断了mek1驱动的GAL4-ELK1 （erk1 /2调控的转录因子）的激活，但无法阻断mek5驱动的GAL4-MEF2D （erk5调控的转录因子）的激活。这些结果表明，即使在过表达的情况下，DUSP6也不能使ERK5失活，证实它确实是erk1 /2特异性DUSP。(C) 2008爱思唯尔公司版权所有。
Extracellular signal-regulated kinase-1 and -2 (ERK1/2) are activated by dual threonine and tyrosine phosphorylation of a TEY motif The highly related kinase ERK5 is also activated by phosphorylation at a TEY motif. Inactivation of ERK1/2 is achieved by distinct members of the dual-specificity protein phosphatase (DUSP) family, which are responsible for the specific, regulated de-phosphorylation of the TEY motif. These include both nuclear (DUSP5) and cytoplasmic (DUSP6) enzymes. DUSP6, a candidate tumour suppressor gene, is thought to be highly specific for inactivation of ERK1/2 but several reports have suggested that it may also inactivate ERK5. Here we have compared the ability of DUSP6 to regulate the ERK1/2 and ERK5 protein kinases. We find that DUSP6 binds to ERK1/2 in both yeast and human cells but fails to bind to ERK5. Recombinant ERK2 can induce catalytic activation of DUSP6 whereas ERK5 cannot. Ectopic expression of DUSP6 can de-phosphorylate a co-expressed ERK2 construct but does not de-phosphorylate ERK5. Finally, expression of DUSP6 blocks the MEK1-driven activation of GAL4-ELK1, an ERK1/2-regulated transcription factor, but fails to block the MEK5-driven activation of GAL4-MEF2D, an ERK5-regulated transcription factor. These results demonstrate that even upon over-expression DUSP6 fails to inactivate ERK5, confirming that it is indeed an ERK1/2-specific DUSP. (C) 2008 Elsevier Inc. All rights reserved.