Miyagi Cancer Center Research Institute, Natori, Japan.
Biochem Biophys Res Commun. 2010 Mar 5;393(2):201-6. doi: 10.1016/j.bbrc.2010.01.097. Epub 2010 Feb 1.
MAPK phosphatase-7 (MKP-7) was identified as a JNK-specific phosphatase. However, despite its high specificity for JNK, MKP-7 interacts also with ERK. We previously showed that as a physiological consequence of their interaction, activated ERK phosphorylates MKP-7 at Ser-446, and stabilizing MKP-7. In the present study, we analyzed MKP-7 function in activation of ERK. A time-course experiment showed that both MKP-7 and its phosphatase-dead mutant prolonged mitogen-induced ERK phosphorylation, suggesting that MKP-7 functions as a scaffold for ERK. An important immunohistological finding was that nuclear translocation of phospho-ERK following PMA stimulation was blocked by co-expressed MKP-7 and, moreover, that phospho-ERK co-localized with MKP-7 in the cytoplasm. Reporter gene analysis indicated that MKP-7 blocks ERK-mediated transcription. Overall, our data indicate that MKP-7 down-regulates ERK-dependent gene expression by blocking nuclear accumulation of phospho-ERK.
丝裂原活化蛋白激酶磷酸酶-7（MKP-7）被鉴定为一种 JNK 特异性磷酸酶。然而，尽管 MKP-7 对 JNK 具有高度特异性，但它也与 ERK 相互作用。我们之前的研究表明，作为它们相互作用的生理后果，激活的 ERK 在 Ser-446 位点使 MKP-7 磷酸化，从而稳定 MKP-7。在本研究中，我们分析了 MKP-7 在 ERK 激活中的功能。时程实验表明，MKP-7 及其磷酸酶失活突变体均延长有丝分裂原诱导的 ERK 磷酸化，表明 MKP-7 作为 ERK 的支架发挥作用。一个重要的免疫组织化学发现是，PMA 刺激后磷酸化 ERK 的核易位被共表达的 MKP-7 阻断，并且磷酸化 ERK 与细胞质中的 MKP-7 共定位。报告基因分析表明，MKP-7 通过阻断磷酸化 ERK 的核积累来阻断 ERK 介导的转录。总体而言，我们的数据表明，MKP-7 通过阻断磷酸化 ERK 的核积累来下调 ERK 依赖性基因表达。
