Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation
Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation
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DOI：
10.1038/sj.cdd.4401647
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发表时间：
2005-06-01
影响因子：
12.4
通讯作者：
Medema, JP
中科院分区：
文献类型：
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作者：
Hendriks, J;Planelles, L;Medema, JP
APRIL是一种增殖诱导配体，是肿瘤坏死因子（TNF）家族的成员，由各种类型的肿瘤表达，并影响其体外和体内生长。两种受体，跨膜激活因子和亲环蛋白配体相互作用因子（TACI）和B细胞成熟抗原（BCMA），结合APRIL，但都不是肿瘤促进作用所必需的，这表明存在第三种受体。在这里，我们报告APRIL特异性结合肿瘤细胞表面的硫酸乙酰肝素蛋白聚糖（HSPG）。这种结合由硫酸肝素侧链介导，并可被肝素抑制。重要的是，BCMA和HSPG不竞争，但可以同时结合APRIL，这表明APRIL中的不同区域对于任何一种相互作用都是至关重要的。在协议中，在一个假定的硫酸肝素结合基序，这不是TNF折叠的一部分，三个赖氨酸的突变，破坏与HSPG的相互作用，而结合BCMA不受影响。最后，尽管APRIL与HSPG的相互作用不影响APRIL诱导的T细胞增殖，但它对其肿瘤生长促进活性至关重要。因此，我们得出结论，要么HSPG作为APRIL的受体，要么HSPG结合允许APRIL与促进肿瘤生长的受体相互作用。
APRIL, a proliferation-inducing ligand, is a member of the tumor necrosis factor (TNF) family that is expressed by various types of tumors and influences their growth in vitro and in vivo. Two receptors, transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen ( BCMA), bind APRIL, but neither is essential for the tumor-promoting effects, suggesting that a third receptor exists. Here, we report that APRIL specifically binds to heparan sulfate proteoglycans ( HSPG) on the surface of tumor cells. This binding is mediated by the heparin sulfate side chains and can be inhibited by heparin. Importantly, BCMA and HSPG do not compete, but can bind APRIL simultaneously, suggesting that different regions in APRIL are critical for either interaction. In agreement, mutation of three lysines in a putative heparin sulfate-binding motif, which is not part of the TNF fold, destroys interaction with HSPG, while binding to BCMA is unaffected. Finally, whereas interaction of APRIL with HSPG does not influence APRIL-induced proliferation of T cells, it is crucial for its tumor growth-promoting activities. We therefore conclude that either HSPG serve as a receptor for APRIL or that HSPG binding allows APRIL to interact with a receptor that promotes tumor growth.