Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused
Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused
复制标题
蛋白磷酸酶 4 通过融合抑制子的去磷酸化促进 Hedgehog 信号传导
DOI：
10.1038/s41419-020-02843-w
复制
发表时间：
2020-08-11
影响因子：
9
通讯作者：
Yue, Shen
中科院分区：
文献类型：
--
作者：
Liao, Hengqing;Cai, Jing;Yue, Shen
Suppressor of fused（Sufu）的可逆磷酸化是Sonic Hedgehog（Shh）信号转导所必需的。腐乳在蛋白激酶A（PKA）和糖原合成酶激酶3 β（GSK 3 β）的双重磷酸化下稳定。其磷酸化随着Shh信号传导的激活而减少。利用蛋白质组学的方法，我们鉴定了腐乳蛋白磷酸酶4调节亚基2（Ppp4r2），它是腐乳蛋白的一个相互作用蛋白。Shh信号促进了这两种蛋白在细胞核中的相互作用，Ppp4也促进了Sufu的去磷酸化，导致其降解并增强了Gli1的转录活性。最后，Ppp4介导的腐乳去磷酸化促进髓母细胞瘤肿瘤细胞的增殖，Ppp4的表达与Shh亚型髓母细胞瘤中Shh通路靶基因的上调呈正相关，强调了这种调节在Shh信号传导中的重要作用。
Reversible phosphorylation of Suppressor of fused (Sufu) is essential for Sonic Hedgehog (Shh) signal transduction. Sufu is stabilized under dual phosphorylation of protein kinase A (PKA) and glycogen synthase kinase 3 beta (GSK3 beta). Its phosphorylation is reduced with the activation of Shh signaling. However, the phosphatase in this reversible phosphorylation has not been found. Taking advantage of a proteomic approach, we identified Protein phosphatase 4 regulatory subunit 2 (Ppp4r2), an interacting protein of Sufu. Shh signaling promotes the interaction of these two proteins in the nucleus, and Ppp4 also promotes dephosphorylation of Sufu, leading to its degradation and enhancing the Gli1 transcriptional activity. Finally, Ppp4-mediated dephosphorylation of Sufu promotes proliferation of medulloblastoma tumor cells, and expression of Ppp4 is positively correlated with up-regulation of Shh pathway target genes in the Shh-subtype medulloblastoma, underscoring the important role of this regulation in Shh signaling.