Malbon Craig C
Department of Pharmacology, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
Front Biosci. 2004 May 1;9:1048-58. doi: 10.2741/1308.
The superfamily of membrane receptors that signal via heterotrimeric G-proteins includes more than 1500 members, classified into five basic groups, representing about 5-10% of the human genome. These G-protein-coupled receptors operate through a comparatively smaller group of heterotrimeric G-protein family of approximately 20 members, each displaying an alpha subunit that binds and hydrolyzes GTP in combination with the beta-/gamma-subunit complex that is largely non-dissociable in vivo. Frizzleds represent the cell membrane receptors for a family of secreted glycoprotein ligands termed "Wnts" that play essential roles in development, including cell fate, adhesion, polarity, migration, and proliferation. Based upon a compelling set of experimental observations about the structure and downstream signaling of Wnt-Frizzled signaling, one can only conclude that Frizzleds are true members of the GPCR family and require heterotrimeric G-proteins to propagate signals from the Wnts to well-known effectors, including beta-catenin stabilization, mobilization of intracellular Ca2+, and activation of cyclic GMP phosphodiesterase. Careful study of primary structure of Frizzleds reveal heptihelical, 7-transmembrane segments, characteristic of GPCRs. Chimeric forms of Frizzleds, making use of the cytoplasmic domains of Frizzleds, substituted into the exofacial and transmembrane segments of the prototypic GPCR beta2-adrenergic receptor are functional and display the well-known GTP-shift in receptor affinity. Suppression of specific G-protein subunits suppress the ability of chimeric as well as authentic Frizzled-1 and Frizzled-2 to signal to their canonical pathways upon activation. The involvement of beta-arrestin, an important regulator of GPCR signaling, in Frizzled signaling is, therefore, not unexpected. Recognition of the GPCR character of Frizzled enables a more broad understanding of these receptors and of their mechanisms of downstream signaling.
通过异源三聚体G蛋白发出信号的膜受体超家族包含1500多个成员，分为五个基本组，约占人类基因组的5-10%。这些G蛋白偶联受体通过一组相对较小的约20个成员的异源三聚体G蛋白家族发挥作用，每个G蛋白都有一个α亚基，它与β/γ亚基复合物结合并水解GTP，β/γ亚基复合物在体内基本不可解离。卷曲蛋白代表了一类分泌型糖蛋白配体“Wnt”的细胞膜受体，Wnt在发育过程中发挥着重要作用，包括细胞命运、黏附、极性、迁移和增殖。基于一系列关于Wnt-卷曲蛋白信号传导的结构和下游信号传导的令人信服的实验观察结果，人们只能得出结论，卷曲蛋白是GPCR家族的真正成员，需要异源三聚体G蛋白将Wnt的信号传递给包括β-连环蛋白稳定、细胞内Ca2+动员和环鸟苷酸磷酸二酯酶激活在内的知名效应器。对卷曲蛋白一级结构的仔细研究揭示了七螺旋的7个跨膜片段，这是GPCR的特征。利用卷曲蛋白的胞质结构域构建的卷曲蛋白嵌合体，替代到原型GPCRβ2-肾上腺素能受体的胞外侧和跨膜片段中是有功能的，并显示出受体亲和力中众所周知的GTP位移。抑制特定的G蛋白亚基会抑制嵌合体以及天然卷曲蛋白-1和卷曲蛋白-2在激活后向其经典途径发出信号的能力。因此，β-抑制蛋白（GPCR信号传导的重要调节因子）参与卷曲蛋白信号传导并不意外。认识到卷曲蛋白的GPCR特性有助于更广泛地理解这些受体及其下游信号传导机制。
