Soluble Heparin and Heparan Sulfate Glycosaminoglycans Interfere with Sonic Hedgehog Solubilization and Receptor Binding
Soluble Heparin and Heparan Sulfate Glycosaminoglycans Interfere with Sonic Hedgehog Solubilization and Receptor Binding
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DOI：
10.3390/molecules24081607
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发表时间：
2019-04-02
期刊：
影响因子：
4.6
通讯作者：
Grobe, Kay
中科院分区：
文献类型：
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作者：
Manikowski, Dominique;Jakobs, Petra;Grobe, Kay
Sonic hedgehog （Shh）信号在许多上皮性癌症中起肿瘤促进作用。癌细胞产生可溶性Shh，向远处表达受体补丁（Ptc）的基质细胞发出信号。这些接收细胞通过产生其他促进癌细胞生长的可溶性因子来做出反应，形成一个正反馈循环。为了干扰增强的Shh信号，我们检测了肝素和硫酸肝素（HS）多糖阻断Shh溶解和Ptc受体结合的潜力。我们在体外和体内证实，n端cardina - weintraub （CW）氨基酸基序的蛋白水解裂解是Shh溶解和功能的先决条件。与可溶性肝素或HS与Shh CW靶基序的结合一致，这两种多糖都损害了Shh的蛋白水解加工和源细胞的释放。我们还发现，HS和肝素结合并阻断了另一组基本氨基酸，这些氨基酸是Shh与接收细胞上Ptc受体未受损结合所必需的。这两种Shh活性下调模式更多地依赖于HS的大小和总电荷，而不是特定的HS硫酸修饰。我们认为，肝素寡糖干扰HS在Shh释放和接收中的生理作用可能用于扩大研究领域，以药物干预促肿瘤Shh功能。
Sonic hedgehog (Shh) signaling plays a tumor-promoting role in many epithelial cancers. Cancer cells produce soluble a Shh that signals to distant stromal cells that express the receptor Patched (Ptc). These receiving cells respond by producing other soluble factors that promote cancer cell growth, generating a positive feedback loop. To interfere with reinforced Shh signaling, we examined the potential of defined heparin and heparan sulfate (HS) polysaccharides to block Shh solubilization and Ptc receptor binding. We confirm in vitro and in vivo that proteolytic cleavage of the N-terminal Cardin-Weintraub (CW) amino acid motif is a prerequisite for Shh solubilization and function. Consistent with the established binding of soluble heparin or HS to the Shh CW target motif, both polysaccharides impaired proteolytic Shh processing and release from source cells. We also show that HS and heparin bind to, and block, another set of basic amino acids required for unimpaired Shh binding to Ptc receptors on receiving cells. Both modes of Shh activity downregulation depend more on HS size and overall charge than on specific HS sulfation modifications. We conclude that heparin oligosaccharide interference in the physiological roles of HS in Shh release and reception may be used to expand the field of investigation to pharmaceutical intervention of tumor-promoting Shh functions.