PPP3CC feedback regulates IP3-Ca2+ pathway through preventing ITPKC degradation.
PPP3CC feedback regulates IP3-Ca2+ pathway through preventing ITPKC degradation.
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DOI：
10.2741/4153
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发表时间：
2013-06
期刊：
影响因子：
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通讯作者：
Pu Li;Peng Zhang;Ying Lin;Jingxuan Shan;Jiaqi Wang;T. Zhou;Zhenggang Zhu;K. Huo
中科院分区：
文献类型：
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作者：
Pu Li;Peng Zhang;Ying Lin;Jingxuan Shan;Jiaqi Wang;T. Zhou;Zhenggang Zhu;K. Huo
ITPKC是川崎病的一个易感基因，它编码一种激酶，该激酶负调控细胞内Ca2+水平，并通过磷酸化IP3抑制钙调磷酸酶依赖性NFAT的激活。在这项研究中，我们利用酵母双杂交鉴定了一种新的itpkc相互作用蛋白PPP3CC。GST下拉和共免疫沉淀实验进一步证实了这种相互作用，荧光显微镜显示两种蛋白在细胞质中共定位。我们的功能研究表明PPP3CC积极影响ITPKC的蛋白水平，可能是通过抑制ITPKC的磷酸化，从而阻止ITPKC进行泛素介导的需要磷酸化的蛋白降解。重要的是，PPP3CC的蛋白水平与IP3的细胞水平呈负相关，表明PPP3CC在IP3- ca2 +信号通路中具有调节作用。
ITPKC, a susceptibility gene of Kawasaki disease, encodes a kinase that negatively regulates intracellular Ca2+ level and inhibits calcineurin-dependent activation of NFAT by phosphorylating IP3. In this study, we identified a novel ITPKC-interacting protein, namely PPP3CC, using yeast two-hybrid. This interaction was further confirmed by GST pull-down and co-immunoprecipitation assays, and fluorescent microscopy showed co-localization of both proteins in the cell cytoplasm. Our functional studies demonstrated that PPP3CC positively influences the protein level of ITPKC, likely by inhibiting phosphorylation of ITPKC and consequently preventing ITPKC from ubiquitin-mediated protein degradation which requires phosphorylation. Importantly, the protein level of PPP3CC negatively correlates with the cellular level of IP3, suggesting a regulatory role of PPP3CC in the IP3-Ca2+ signaling pathway.