The Hedgehog signaling network
The Hedgehog signaling network
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DOI：
10.1002/ajmg.a.20495
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发表时间：
2003-11-15
影响因子：
2
通讯作者：
Cohen, MM
中科院分区：
文献类型：
--
作者：
Cohen, MM
在刺猬信号网络中，突变导致各种表型，包括前脑无裂、痣样基底细胞癌综合征、Pallister-Hall综合征、Greig头多并指（趾）畸形、Rubinstein-Taybi综合征、孤立性基底细胞癌和髓母细胞瘤等。活性Hedgehog配体是用C-末端胆固醇部分和N-末端棕榈酸酯修饰的双脂质。Hedgehog从信号细胞到应答细胞的转运通过三种机制进行：1）。形成使其可溶的多聚体Hedgehog; 2）. Dispatched在从信号传导细胞释放脂质锚定蛋白中的功能;和3）.通过Tout-velu依赖性的硫酸乙酰肝素蛋白聚糖合成而穿过应答细胞的质膜。在响应细胞中，活性Hedgehog与其受体Patched结合，Patched是一种12次跨膜蛋白，其释放Smoothened，一种相邻的7次跨膜蛋白，用于下游信号传导。Patched和Smoothened可以响应于活性Hedgehog配体在质膜和内吞囊泡之间反向穿梭。在下游信号传导中，Cubitus interruptus（脊椎动物中的Gli蛋白）、Costal 2、Fused和Fused的抑制子形成四聚体复合物。Cubitus interruptus是一种双功能转录调节因子。在缺乏活性Hedgehog配体的情况下，产生截短的转录阻遏物，其结合靶基因并阻断其转录。在活性Hedgehog配体的存在下，全长转录激活因子结合靶基因并上调其转录。靶基因包括Wingless（脊椎动物中的Wnt基因家族）、Decapentaplegic（脊椎动物中的骨形态发生蛋白）和Patched。Patched表达的上调，导致细胞膜上的Patched蛋白，隔离Hedgehog并限制其扩散到产生它的细胞之外。因此，通过Hedgehog和Patched的拮抗作用产生平衡，其相对浓度彼此交替。还讨论了对刺猬信号网络至关重要的更多因素：Megalin，Rab 23，Hip，GAS 1，PKA，GSK 3，CK 1，Slimb，SAP 18和CBP。(C)2003 Wiley-Liss，Inc.
In the hedgehog signaling network, mutations result in various phenotypes, including, among others, holoprosencephaly, nevoid basal cell carcinoma syndrome, Pallister-Hall syndrome, Greig cephalopolysyndactyly, Rubinstein-Taybi syndrome, isolated basal cell carcinoma, and medulloblastoma. Active Hedgehog ligand is double lipid modified with a C-terminal cholesterol moiety and an N-terminal palmitate. Transport active Hedgehog from the signaling cell to the responding cell occurs through three mechanisms: 1). formation of multimeric Hedgehog which makes it soluble; 2). function of Dispatched in releasing the lipid-anchored protein from the signaling cell; and 3). movement across the plasma membrane of the responding cell by Tout-velu-dependent synthesis of heparan sulfate proteoglycan. In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling. Patched and Smoothened may shuttle oppositely between the plasma membrane and endocytic vesicles in response to active Hedgehog ligand. In downstream signaling, Cubitus interruptus (Gli proteins in vertebrates), Costal 2, Fused, and Suppressor of Fused form a tetrameric complex. Cubitus interruptus is a bifunctional transcription regulator. In the absence of active Hedgehog ligand, a truncated transcriptional repressor is generated that binds target genes and blocks their transcription. In the presence of active Hedgehog ligand, a full length transcriptional activator binds target genes and upregulates their transcription. Target genes include Wingless (Wnt gene family in vertebrates), Decapentaplegic (Bone Morphogenetic Proteins in vertebrates), and Patched. The upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters Hedgehog and limits its spread beyond the cells in which it is produced. Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. Many more factors that are essential for the hedgehog signaling network are also discussed: Megalin, Rab23, Hip, GAS1, PKA, GSK3, CK1, Slimb, SAP18, and CBP. (C) 2003 Wiley-Liss, Inc.