The role of glypicans in Wnt inhibitory factor-1 activity and the structural basis of Wif1's effects on Wnt and Hedgehog signaling.
The role of glypicans in Wnt inhibitory factor-1 activity and the structural basis of Wif1's effects on Wnt and Hedgehog signaling.
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DOI：
10.1371/journal.pgen.1002503
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Blair SS
中科院分区：
文献类型：
--
作者：
Avanesov A;Honeyager SM;Malicki J;Blair SS
细胞命运的正确分配依赖于对Wnt和Hedgehog(HH)信号的正确解释。WNT抑制因子-1(WIF1)家族成员是这些细胞外信号通路的分泌型调节器。脊椎动物WIF1结合WNT并抑制它们的信号转导，但其果蝇的黑腹果蝇正向同源移位(SHF)结合HH并扩大了黑腹果蝇翅膀发育中HH的活动范围。SHF的活性被认为依赖于加强HH和Glypica HSPG之间的相互作用。利用斑马鱼胚胎和黑腹斑马鱼翅膀提供的异源系统，我们报道了Glypica HSPGs对斑马鱼Wif1抑制Wnt活性的贡献，以及导致Wif1和SHF特异性差异的蛋白质结构域。我们发现Wif1增强了Wnt和Glypicans之间的相互作用，调节了Glypicans对Wnt抑制的双相作用；相反，Glypicans和Wif1的Glypcan结合的“表皮生长因子样”结构域是Wif1‘S充分抑制Wnt的必需的。使用Wif1和SHF之间的嵌合结构来研究它们对Wnt和HH信号的特异性。完全抑制Wnt需要Wif1的“WIF”结构域，以及Wif1或SHF的HSPG结合的EGF样结构域。HH信号的完全促进需要SHF的EGF样结构域和Wif1或SHF的WIF结构域。Wif1的WIF结构域能够增加SHF的EGF结构域的促HH活性，这表明它能够与HH相互作用。事实上，全长Wif1影响黑腹隐翅虫HH的分布和信号转导，尽管幅度很小，这表明Wif1可能是脊椎动物HH信号的调节者。在发育中的生物体中，细胞为了制造适当图案的组织而在不同的命运之间做出选择，而对这些选择的错误调控可能会导致发育缺陷和癌症。细胞经常做出这些决定，因为从邻近细胞收到的信号，例如那些由Wnt和Hedgehog(HH)家族分泌的信号蛋白介导的信号。虽然信号可以由细胞表达的信号或受体蛋白的水平来调节，但另一种水平的控制是由蛋白质施加的，这些蛋白质结合细胞外的信号蛋白，抑制或促进信号过程。在果蝇黑腹果蝇中，分泌的转移蛋白被证明结合HH并增加HH信号，可能是通过加强HH与海豚家族细胞表面蛋白之间的相互作用。我们提供的证据表明，脊椎动物中的移位WNT抑制因子-1(Wif1)通过类似的机制抑制WNT的活性，以一种将WNT与其受体隔离的方式加强WNT与龟头之间的相互作用。我们还研究了Wif1和Shift分别针对Wnt和HH信号的特异性的结构基础，并提供了证据表明，尽管Wif1是Wnt活性的有效抑制剂，但Wif1影响黑腹葡萄球菌的HH信号。
Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican-binding “EGF-like” domains of Wif1 are required for Wif1's full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the “WIF” domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. Full promotion of Hh signaling requires both the EGF-like domains of Shf and the WIF domains of either Wif1 or Shf. That the Wif1 WIF domain can increase the Hh promoting activity of Shf's EGF domains suggests it is capable of interacting with Hh. In fact, full-length Wif1 affected distribution and signaling of Hh in D. melanogaster, albeit weakly, suggesting a possible role for Wif1 as a modulator of vertebrate Hh signaling. In developing organisms, cells choose between alternative fates in order to make appropriately patterned tissues, and misregulation of those choices can underlie both developmental defects and cancers. Cells often make these decisions because of signals received from neighboring cells, such as those mediated by the secreted signaling proteins of the Wnt and Hedgehog (Hh) families. While signaling can be regulated by the levels of signaling or receptor proteins expressed by cells, another level of control is exerted by proteins that bind signaling proteins outside of cells and either inhibit or promote the signaling process. In the fruitfly Drosophila melanogaster, the secreted Shifted protein has been shown to bind Hh and to increase Hh signaling, likely by reinforcing interactions between Hh and cell surface proteins of the glypican family. We provide evidence that the vertebrate homolog of Shifted, Wnt Inhibitory Factor-1 (Wif1), inhibits Wnt activity by a similar mechanism, reinforcing interactions between Wnts and glypicans in a manner that sequesters Wnts from their receptors. We also examine the structural basis for the specificities of Wif1 and Shifted for Wnt and Hh signaling, respectively, and provide evidence that Wif1, although a potent inhibitor of Wnt activity, influences D. melanogaster Hh signaling.
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