Sun Wenjing, Yu Yang, Dotti Gianpietro, Shen Tao, Tan Xiaojie, Savoldo Barbara, Pass Amy K, Chu Meijin, Zhang Dekai, Lu Xiongbin, Fu Songbin, Lin Xia, Yang Jianhua
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States.
Cell Signal. 2009 Jan;21(1):95-102. doi: 10.1016/j.cellsig.2008.09.012. Epub 2008 Oct 1.
IKKbeta serves as a central intermediate signaling molecule in the activation of the NF-kappaB pathway. However, the precise mechanism for the termination of IKKbeta activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKKbeta phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. PPM1A and PPM1B associate with the phosphorylated form of IKKbeta, and the interaction between PPM1A/PPM1B and IKKbeta is induced by TNFalpha in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNFalpha-induced IKKbeta phosphorylation, NF-kappaB nuclear translocation and NF-kappaB-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNFalpha-mediated NF-kappaB activation through dephosphorylating and inactivating IKKbeta.
IKKβ在核因子κB（NF-κB）信号通路的激活过程中作为核心中间信号分子发挥作用。然而，IKKβ活性终止的确切机制仍未完全明确。我们采用功能基因组学方法，鉴定出两种蛋白丝氨酸/苏氨酸磷酸酶，即PPM1A和PPM1B，作为IKKβ磷酸酶。PPM1A或PPM1B的过表达导致IKKβ的丝氨酸177和丝氨酸181位点去磷酸化，并终止IKKβ诱导的NF-κB激活。PPM1A和PPM1B与磷酸化形式的IKKβ相互作用，并且在细胞中，PPM1A/PPM1B与IKKβ之间的相互作用由肿瘤坏死因子α（TNFα）短暂诱导。此外，敲低PPM1A和PPM1B的表达会增强TNFα诱导的IKKβ磷酸化、NF-κB核转位以及NF-κB依赖性基因表达。这些数据表明，PPM1A和PPM1B通过使IKKβ去磷酸化并使其失活，在TNFα介导的NF-κB激活的终止过程中发挥重要作用。
