PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation.
PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation.
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DOI：
10.1016/j.cellsig.2008.09.012
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发表时间：
2009-01
影响因子：
4.8
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Sun W;Yu Y;Dotti G;Shen T;Tan X;Savoldo B;Pass AK;Chu M;Zhang D;Lu X;Fu S;Lin X;Yang J
IKKβ在NF-κB通路的激活中作为中心中间信号分子。然而，IKKβ活性终止的确切机制尚不完全清楚。使用功能基因组方法，我们已经鉴定出两种蛋白丝氨酸/苏氨酸磷酸酶PPM1A和PPM1B作为IKKβ磷酸酶。PPM1A或PPM1B的过表达导致IKKβ在Ser177和Ser181处去磷酸化，并终止IKKβ诱导的NF-κB活化。PPM1A和PPM1B与IKKβ的磷酸化形式相关联，并且PPM1A/PPM1B与IKKβ之间的相互作用是由TNFα在细胞中短暂诱导的。此外，敲低PPM1A和PPM1B表达可增强tnf α诱导的IKKβ磷酸化、NF-κB核易位和NF-κB依赖基因的表达。这些数据表明PPM1A和PPM1B通过IKKβ的去磷酸化和失活，在终止tnf α介导的NF-κB活化中发挥重要作用。
IKKβ serves as a central intermediate signaling molecule in the activation of the NF-κB pathway. However, the precise mechanism for the termination of IKKβ activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKKβ phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKβ at Ser177 and Ser181 and termination of IKKβ-induced NF-κB activation. PPM1A and PPM1B associate with the phosphorylated form of IKKβ, and the interaction between PPM1A/PPM1B and IKKβ is induced by TNFα in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNFα-induced IKKβ phosphorylation, NF-κB nuclear translocation and NF-κB-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNFα-mediated NF-κB activation through dephosphorylating and inactivating IKKβ.
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