Hot Belma, Valnohova Jana, Arthofer Elisa, Simon Katharina, Shin Jaekyung, Uhlén Mathias, Kostenis Evi, Mulder Jan, Schulte Gunnar
Section of Receptor Biology & Signaling, Dept. Physiology & Pharmacology, Karolinska Institutet, S17177 Stockholm, Sweden.
Section of Receptor Biology & Signaling, Dept. Physiology & Pharmacology, Karolinska Institutet, S17177 Stockholm, Sweden; Section on Molecular Signal Transduction Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35A Convent Drive, MSC 3752, Bethesda, MD 20892-3752, USA.
Cell Signal. 2017 Apr;32:93-103. doi: 10.1016/j.cellsig.2017.01.023. Epub 2017 Jan 24.
Among the 10 Frizzled (FZD) isoforms belonging to the Class F of G protein-coupled receptors (GPCRs), FZD remains the most enigmatic. FZD shows homology to FZD and FZD and was previously implicated in both β-catenin-dependent and -independent signalling. In normal tissue, FZD levels are generally very low; however, its upregulation in synovial carcinoma has attracted some attention for therapy. Our findings identify FZD as a receptor interacting with and signalling through the heterotrimeric G protein Gα but not Gα Gα Gα Gα, or Gα. Stimulation with the FZD agonist WNT induced the dissociation of the Gα protein from FZD, and led to global Gα-dependent cell changes assessed by dynamic mass redistribution measurements. Furthermore, we show that FZD mediates Gα activation-dependent induction of YAP/TAZ transcriptional activity. In addition, we show a distinct expression of FZD in embryonic CNS endothelial cells at E11.5-E14.5. Given the well-known importance of Gα signalling for the development of the vascular system, the selective expression of FZD in brain vascular endothelial cells points at a potential role of FZD-Gα signalling in CNS angiogenesis.
在属于G蛋白偶联受体（GPCR）F类的10种卷曲蛋白（FZD）亚型中，FZD仍然是最神秘的。FZD与FZD和FZD具有同源性，先前被认为与β-连环蛋白依赖性和非依赖性信号传导有关。在正常组织中，FZD水平通常非常低；然而，其在滑膜癌中的上调已引起治疗方面的一些关注。我们的研究结果确定FZD是一种与异源三聚体G蛋白Gα相互作用并通过其信号传导的受体，但不与Gα、Gα、Gα、Gα或Gα相互作用。用FZD激动剂WNT刺激可诱导Gα蛋白从FZD解离，并导致通过动态质量再分布测量评估的全局Gα依赖性细胞变化。此外，我们表明FZD介导YAP/TAZ转录活性的Gα激活依赖性诱导。此外，我们显示FZD在胚胎第11.5至14.5天的中枢神经系统内皮细胞中有独特表达。鉴于Gα信号传导对血管系统发育的众所周知的重要性，FZD在脑血管内皮细胞中的选择性表达表明FZD-Gα信号传导在中枢神经系统血管生成中具有潜在作用。
