Lai Maria B, Zhang Chi, Shi Jianli, Johnson Verity, Khandan Lavan, McVey John, Klymkowsky Michael W, Chen Zhe, Junge Harald J
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
Cell Rep. 2017 Jun 27;19(13):2809-2822. doi: 10.1016/j.celrep.2017.06.004.
Accessory proteins in Frizzled (FZD) receptor complexes are thought to determine ligand selectivity and signaling amplitude. Genetic evidence indicates that specific combinations of accessory proteins and ligands mediate vascular β-catenin signaling in different CNS structures. In the retina, the tetraspanin TSPAN12 and the ligand norrin (NDP) mediate angiogenesis, and both genes are linked to familial exudative vitreoretinopathy (FEVR), yet the molecular function of TSPAN12 remains poorly understood. Here, we report that TSPAN12 is an essential component of the NDP receptor complex and interacts with FZD4 and NDP via its extracellular loops, consistent with an action as co-receptor that enhances FZD4 ligand selectivity for NDP. FEVR-linked mutations in TSPAN12 prevent the incorporation of TSPAN12 into the NDP receptor complex. In vitro and in Xenopus embryos, TSPAN12 alleviates defects of FZD4 M105V, a mutation that destabilizes the NDP/FZD4 interaction. This study sheds light on the poorly understood function of accessory proteins in FZD signaling.
卷曲蛋白（FZD）受体复合物中的辅助蛋白被认为可决定配体选择性和信号强度。遗传学证据表明，辅助蛋白和配体的特定组合在不同的中枢神经系统结构中介导血管β-连环蛋白信号传导。在视网膜中，四跨膜蛋白TSPAN12和配体诺里蛋白（NDP）介导血管生成，且这两个基因均与家族性渗出性玻璃体视网膜病变（FEVR）相关，但TSPAN12的分子功能仍知之甚少。在此，我们报道TSPAN12是NDP受体复合物的重要组成部分，并通过其细胞外环与FZD4和NDP相互作用，这与作为共受体增强FZD4对NDP的配体选择性的作用一致。TSPAN12中与FEVR相关的突变会阻止TSPAN12掺入NDP受体复合物。在体外和非洲爪蟾胚胎中，TSPAN12可缓解FZD4 M105V的缺陷，该突变会破坏NDP/FZD4相互作用。这项研究揭示了FZD信号传导中辅助蛋白鲜为人知的功能。
