Regulation of Hedgehog signaling: a complex story
Regulation of Hedgehog signaling: a complex story
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DOI：
10.1016/j.bcp.2004.01.002
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发表时间：
2004-03-01
影响因子：
5.8
通讯作者：
Robbins, DJ
中科院分区：
文献类型：
--
作者：
Ogden, SK;Ascano, M;Robbins, DJ
Hedgehog(HH)信号转导通路在发育过程中起着重要的指导作用。人类HH信号成分的激活突变易导致多种类型的肿瘤，并在发生在广泛器官的散发性肿瘤中观察到。通过以偏胃果蝇为模式生物的研究，已经获得了对HH信号调节的多种见解。在果蝇中，转录因子Cubitus interruptus(Ci)的调节是HH途径的最终目标。CI是通过膜蛋白补丁(PTC)和平滑蛋白(Smo)与细胞内Hedgehog信号复合体(HSC)的通讯来调节的，以响应不同浓度的HH配体。HSC由激动素相关蛋白Cost2(Cos2)、丝氨酸-苏氨酸蛋白激酶、融合蛋白(FU)和Ci组成。在没有HH刺激的情况下，HSC参与将Ci加工成截断的阻遏蛋白。作为对HH与PTC结合的反应，Ci的加工被阻止，以允许全长Ci激活蛋白的积累(S)。不同浓度的HH配体刺激不同强度的Ci转录激活因子的产生，从而促进靶基因的不同亚组的激活。PTC和Smo在不同的配基浓度下与HSC进行通讯以调节Ci功能的机制(S)尚未完全阐明。在这里，我们回顾了关于单个HH信号成分的调节的已知情况，集中在HH信号通过Smo传播到HSC的机制上。(C)2004 Elsevier Inc.保留所有权利。
The Hedgehog (Hh) signal transduction pathway plays critical instructional roles during development. Activating mutations in human Hh signaling components predispose to a variety of tumor types, and have been observed in sporadic tumors occurring in a wide range of organs. Multiple insights into the regulation of Hh signaling have been achieved through studies using Drosophila metanogaster as a model organism. In Drosophila, regulation of the transcription factor Cubitus interruptus (Ci) is the ultimate target of the Hh pathway. Ci is regulated through communication of the membrane proteins Patched (Ptc) and Smoothened (Smo) to the intracellular Hedgehog Signaling Complex (HSC) in response to a graded concentration of Hh ligand. The HSC consists of the Kinesin Related Protein, Costal2 (Cos2), the serine-threonine protein kinase, Fused (Fu) and Ci. In the absence of Hh stimulation, the HSC is involved in processing of Ci to a truncated repressor protein. In response to Hh binding to Ptc, processing of Ci is blocked to allow for accumulation of full-length Ci activator protein(s). Differential concentrations of Hh ligand stimulate production of Ci transcriptional activators of varying strength, which facilitate activation of distinct subsets of target genes. The mechanism(s) by which Ptc and Smo communicate with the HSC in response to differential ligand concentrations to regulate Ci function are not yet fully elucidated. Here, we review what is known about regulation of individual Hh signaling components, concentrating on the mechanisms by which the Hh signal is propagated through Smo to the HSC. (C) 2004 Elsevier Inc. All rights reserved.