Département of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland.
Biochem Pharmacol. 2011 Nov 15;82(10):1311-9. doi: 10.1016/j.bcp.2011.06.005. Epub 2011 Jun 13.
The Wnt/Frizzled signaling pathway plays multiple functions in animal development and, when deregulated, in human disease. The G-protein coupled receptor (GPCR) Frizzled and its cognate heterotrimeric Gi/o proteins initiate the intracellular signaling cascades resulting in cell fate determination and polarization. In this review, we summarize the knowledge on the ligand recognition, biochemistry, modifications and interacting partners of the Frizzled proteins viewed as GPCRs. We also discuss the effectors of the heterotrimeric Go protein in Frizzled signaling. One group of these effectors is represented by small GTPases of the Rab family, which amplify the initial Wnt/Frizzled signal. Another effector is the negative regulator of Wnt signaling Axin, which becomes deactivated in response to Go action. The discovery of the GPCR properties of Frizzled receptors not only provides mechanistic understanding to their signaling pathways, but also paves new avenues for the drug discovery efforts.
Wnt/Frizzled 信号通路在动物发育过程中发挥多种功能，而当其失调时，则会导致人类疾病。G 蛋白偶联受体 (GPCR) Frizzled 及其同源异三聚体 Gi/o 蛋白启动细胞内信号级联反应，导致细胞命运决定和极化。在这篇综述中，我们总结了作为 GPCR 的 Frizzled 蛋白的配体识别、生物化学、修饰和相互作用伙伴的知识。我们还讨论了异三聚体 Go 蛋白在 Frizzled 信号转导中的效应物。这些效应物的一组由 Rab 家族的小 GTPases 组成，它们放大初始 Wnt/Frizzled 信号。另一种效应物是 Wnt 信号的负调节剂 Axin，它在响应 Go 作用时失活。Frizzled 受体的 GPCR 特性的发现不仅为其信号通路提供了机制上的理解，也为药物发现工作开辟了新的途径。
