Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.
Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.
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DOI：
10.1186/1475-4924-1-10
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发表时间：
2002-11-06
影响因子：
--
通讯作者：
Porter JA
中科院分区：
文献类型：
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作者：
Frank-Kamenetsky M;Zhang XM;Bottega S;Guicherit O;Wichterle H;Dudek H;Bumcrot D;Wang FY;Jones S;Shulok J;Rubin LL;Porter JA
Hedgehog（Hh）信号通路对动物发育至关重要，因为它在胚胎发生期间介导多种细胞类型的分化。在成年人中，Hh信号可以被激活以促进组织的维护和修复。此外，Hh通路的刺激已经在神经病模型中显示出治疗功效。然而，Hh信号转导的潜在机制仍然模糊不清：关于通路抑制剂Patched（Ptc）（一种直接结合Hh的多通道跨膜蛋白）和通路激活剂Smoothened（Smo）（一种与G蛋白偶联受体相关的蛋白质，能够在没有Ptc的情况下组成性激活）之间的通信知之甚少。我们已经确定并表征了一种合成的非肽基小分子Hh-Ag，其充当Hh途径的激动剂。这种Hh激动剂在体外促进细胞类型特异性增殖和浓度依赖性分化，而在子宫内，它拯救了Sonic hedgehog无效，但不是Smo无效，小鼠胚胎中的Hh信号传导缺陷。用Hh-Ag、Hh-信号传导拮抗剂环巴胺和新型Hh-信号传导抑制剂Cur 61414的生物化学研究揭示，所有这些化合物的作用不依赖于Hh-蛋白配体和Hh受体Ptc，因为它们各自直接与Smo结合。Smo可以通过合成小分子直接调节其活性。这些研究提出了Hh信号传导可能在体内受内源性小分子调节的可能性，并提供了有效的化合物，用于测试激活Hh信号传导途径在治疗创伤性和慢性退行性疾病中的治疗价值。
The Hedgehog (Hh) signaling pathway is vital to animal development as it mediates the differentiation of multiple cell types during embryogenesis. In adults, Hh signaling can be activated to facilitate tissue maintenance and repair. Moreover, stimulation of the Hh pathway has shown therapeutic efficacy in models of neuropathy. The underlying mechanisms of Hh signal transduction remain obscure, however: little is known about the communication between the pathway suppressor Patched (Ptc), a multipass transmembrane protein that directly binds Hh, and the pathway activator Smoothened (Smo), a protein that is related to G-protein-coupled receptors and is capable of constitutive activation in the absence of Ptc. We have identified and characterized a synthetic non-peptidyl small molecule, Hh-Ag, that acts as an agonist of the Hh pathway. This Hh agonist promotes cell-type-specific proliferation and concentration-dependent differentiation in vitro, while in utero it rescues aspects of the Hh-signaling defect in Sonic hedgehog-null, but not Smo-null, mouse embryos. Biochemical studies with Hh-Ag, the Hh-signaling antagonist cyclopamine, and a novel Hh-signaling inhibitor Cur61414, reveal that the action of all these compounds is independent of Hh-protein ligand and of the Hh receptor Ptc, as each binds directly to Smo. Smo can have its activity modulated directly by synthetic small molecules. These studies raise the possibility that Hh signaling may be regulated by endogenous small molecules in vivo and provide potent compounds with which to test the therapeutic value of activating the Hh-signaling pathway in the treatment of traumatic and chronic degenerative conditions.