Regulation of wingless signaling by the CKI family in Drosophila limb development
Regulation of wingless signaling by the CKI family in Drosophila limb development
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DOI：
10.1016/j.ydbio.2006.07.025
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发表时间：
2006-11-01
影响因子：
2.7
通讯作者：
Jiang, Jin
中科院分区：
文献类型：
--
作者：
Zhang, Lei;Jia, Jianhang;Jiang, Jin
Wg/Wnt信号通路调控着多种发育过程，其功能障碍会导致包括癌症在内的人类疾病。最近的研究表明，酪蛋白激酶I(Casein Kinase I，CKI)家族成员在Wg/Wnt途径中起关键作用。然而，缺乏CKI家族成员参与生理性Wg/Wnt信号事件的遗传学证据。此外，关于一个特定的CKI家族成员是作为该通路的正向调节因子还是负向调节因子发挥作用，也有相互矛盾的报道。在这里，我们研究了7个CKI家族成员在果蝇肢体发育过程中Wg信号转导中的作用。我们发现，增加的CKI epsilon可以刺激Wg信号，而显性负性CKI epsilon突变或无效CKI epsilon突变则抑制Wg信号。相反，通过RNA干扰(RNAi)使CKIα失活会导致异位Wg信号转导。有趣的是，亚型CKI epsilon突变与CKIαRNAi协同诱导异位Wg信号，揭示了CKI epsilon的负面作用。相反，CKIa RNAi增强了CKI epsilon零突变引起的Wg丢失表型，这表明CKIα具有积极的作用。虽然其他五种CKI亚型都不能替代CKIα在Wg途径中的抑制作用，但包括CG12147在内的几种CKI亚型在过度表达的基础上表现出积极的作用。此外，丢失GilGamesh(GISH)/CKI-减弱Wg信号活性。最后，我们提供了包括CKIα和GISH/CKIγ在内的几种CKI亚型可以磷酸化Wg共受体箭头(Art)的证据，这可能至少部分地解释了它们在Wg途径中的积极作用。(C)2006 Elsevier Inc.保留所有权利。
The Wingless (Wg)/Wnt signaling pathway regulates a myriad of developmental processes and its malfunction leads to human disorders including cancer. Recent studies suggest that casein kinase I (CKI) family members play pivotal roles in the Wg/Wnt pathway. However, genetic evidence for the involvement of CKI family members in physiological Wg/Wnt signaling events is lacking. In addition, there are conflicting reports regarding whether a given CKI family member functions as a positive or negative regulator of the pathway. Here we examine the roles of seven CKI family members in Wg signaling during Drosophila limb development. We find that increased CKI epsilon stimulates whereas dominant-negative or a null CKI epsilon mutation inhibits Wg signaling. In contrast, inactivation of CKI alpha by RNA interference (RNAi) leads to ectopic Wg signaling. Interestingly, hypomorphic CKI epsilon mutations synergize with CKI alpha RNAi to induce ectopic Wg signaling, revealing a negative role for CKI epsilon. Conversely, CKIa RNAi enhances the loss-of-Wg phenotypes caused by CKI epsilon null mutation, suggesting a positive role for CKI alpha. While none of the other five CKI isoforms can substitute for CKI alpha in its inhibitory role in the Wg pathway, several CKI isoforms including CG12147 exhibit a positive role based on overexpression. Moreover, loss of Gilgamesh (Gish)/CKI- attenuates Wg signaling activity. Finally, we provide evidence that several CKI isoforms including CKI alpha and Gish/CKI gamma can phosphorylate the Wg coreceptor Arrow (Art), which may account, at least in part, for their positive roles in the Wg pathway. (c) 2006 Elsevier Inc. All rights reserved.