Casein Kinase 2 Promotes Hedgehog Signaling by Regulating both Smoothened and Cubitus Interruptus
Casein Kinase 2 Promotes Hedgehog Signaling by Regulating both Smoothened and Cubitus Interruptus
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DOI：
10.1074/jbc.m110.174565
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发表时间：
2010-11-26
影响因子：
4.8
通讯作者：
Jia, Jianhang
中科院分区：
文献类型：
--
作者：
Jia, Hongge;Liu, Yajuan;Jia, Jianhang
酪蛋白激酶2 （CK2）是一种典型的丝氨酸/苏氨酸激酶，由α和β亚基组成，参与许多细胞和发育过程。在这项研究中，我们证明CK2是Hedgehog （Hh）信号转导通路的正调节因子。我们发现CK2 β RNAi对CK2的失活增强了显性阴性形式Smoothened （Smo）诱导的hh翼表型损失。CK2 β RNAi可减弱Hh诱导的Smo积累并下调Hh靶基因表达，而通过共表达CK2 α和CK2 β来增加CK2活性可增加Smo积累并诱导异位Hh靶基因表达。我们在体外鉴定了Smo中可以被CK2磷酸化的丝氨酸残基。突变这些丝氨酸残基会减弱Smo在体内转导高水平Hh信号活性的能力。此外，我们发现CK2通过调节全长Cubitus-interruptus（Ci）的稳定性在Smo下游发挥着额外的积极作用。CK2 β RNAi促进Ci降解，而共表达CK2 α和CK2 β可延长Ci的半衰期。我们发现CK2可以阻止蛋白酶体对Ci的泛素化和降解。因此，CK2通过调节多种通路组分来促进Hh信号活性。
Casein kinase 2 (CK2) is a typical serine/threonine kinase consisting of alpha and beta subunits and has been implicated in many cellular and developmental processes. In this study, we demonstrate that CK2 is a positive regulator of the Hedgehog (Hh) signal transduction pathway. We found that inactivation of CK2 by CK2 beta RNAi enhances the loss-of-Hh wing phenotype induced by a dominant negative form of Smoothened (Smo). CK2 beta RNAi attenuates Hh-induced Smo accumulation and down-regulates Hh target gene expression, whereas increasing CK2 activity by coexpressing CK2 alpha and CK2 beta increases Smo accumulation and induces ectopic Hh target gene expression. We identified the serine residues in Smo that can be phosphorylated by CK2 in vitro. Mutating these serine residues attenuates the ability of Smo to transduce high level Hh signaling activity in vivo. Furthermore, we found that CK2 plays an additional positive role downstream of Smo by regulating the stability of full-length Cubitus-interruptus(Ci). CK2 beta RNAi promotes Ci degradation whereas coexpressing CK2 alpha and CK2 beta increases the half-life of Ci. We showed that CK2 prevents Ci ubiquitination and degradation by the proteasome. Thus, CK2 promotes Hh signaling activity by regulating multiple pathway components.