Glycosaminoglycans can modulate extracellular localization of the wingless protein and promote signal transduction.
Glycosaminoglycans can modulate extracellular localization of the wingless protein and promote signal transduction.
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DOI：
10.1083/jcb.135.3.819
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发表时间：
1996-11
期刊：
影响因子：
--
通讯作者：
Cumberledge S
中科院分区：
文献类型：
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作者：
Reichsman F;Smith L;Cumberledge S
Wingless 是原癌基因 Wnt-1 的果蝇同源物，编码一种调节附近细胞分化和增殖的分泌糖蛋白。在这里，我们报告了无翼信号在细胞之间传递的生化机制。当在 S2 细胞中表达时，大部分（约 83%）分泌的无翼蛋白 (WG) 通过特定的非共价相互作用与细胞表面和细胞外基质结合。通过添加外源硫酸乙酰肝素和硫酸软骨素糖胺聚糖可以释放束缚的WG。 WG 还以高亲和力直接与肝素琼脂糖珠结合。这些数据表明 WG 可以通过天然存在的硫酸化蛋白聚糖与细胞表面结合。两条证据表明，接收细胞上的胞外糖胺聚糖也在 WG 信号传导中发挥功能性作用。首先，用糖胺聚糖裂解酶处理 WG 反应性细胞，使 WG 活性降低 50%。其次，当 WG 反应性细胞与 1 mM 氯酸盐一起预孵育时（可阻止硫酸化），WG 活性被抑制至接近基础水平。向氯酸盐处理的细胞中添加外源肝素能够恢复 WG 活性。基于这些结果，我们提出 WG 属于生长因子配体，其作用由细胞外蛋白聚糖分子介导。
Wingless, the Drosophila homologue of the proto-oncogene Wnt-1, encodes a secreted glycoprotein that regulates differentiation and proliferation of nearby cells. Here we report on the biochemical mechanism(s) by which the wingless signal is transmitted from cell to cell. When expressed in S2 cells, the majority (approximately 83%) of secreted wingless protein (WG) is bound to the cell surface and extracellular matrix through specific, noncovalent interactions. The tethered WG can be released by addition of exogenous heparan sulfate and chondroitin sulfate glycosaminoglycans. WG also binds directly to heparin agarose beads with high affinity. These data suggest that WG can bind to the cell surface via naturally occurring sulfated proteoglycans. Two lines of evidence indicate that extracellular glycosaminoglycans on the receiving cells also play a functional role in WG signaling. First, treatment of WG-responsive cells with glycosaminoglycan lyases reduced WG activity by 50%. Second, when WG- responsive cells were preincubated with 1 mM chlorate, which blocks sulfation, WG activity was inhibited to near-basal levels. Addition of exogenous heparin to the chlorate-treated cells was able to restore WG activity. Based on these results, we propose that WG belongs to the group of growth factor ligands whose actions are mediated by extracellular proteoglycan molecules.