Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains
Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains
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DOI：
10.1111/febs.12174
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发表时间：
2013-05-01
期刊：
影响因子：
5.4
通讯作者：
Couchman, John R.
中科院分区：
文献类型：
--
作者：
Manon-Jensen, Tina;Multhaupt, Hinke A. B.;Couchman, John R.
多配体聚糖是跨膜硫酸乙酰肝素蛋白聚糖，在细胞增殖、分化、粘附和迁移中起作用。它们通过与广泛的配体以及其他受体相互作用的能力与肿瘤进展中的多种功能相关，这使得它们成为细胞周围微环境中的关键效应子。肿瘤相关基质金属蛋白酶（MMPs）引起的多配体蛋白聚糖的细胞外脱落可能在肿瘤进展中起重要作用。这种胞外域脱落产生可溶性胞外域，其可作为旁分泌或自分泌效应物，或作为完整蛋白聚糖的竞争性抑制剂。本文显示肿瘤相关MMP切割人多配体蛋白聚糖-1和多配体蛋白聚糖-4的胞外域。多配体蛋白聚糖-1和多配体蛋白聚糖-4的两个膜近端区域是有利的MMP切割位点，距离跨膜结构域6和15个残基。其他位点是两种多配体聚糖中硫酸乙酰肝素链取代位点的3540个残基C-末端。通过定点突变证实了多配体蛋白聚糖-1和多配体蛋白聚糖-4中的MT 1-MMP切割位点。这些发现提供了对多配体蛋白聚糖脱落特征的深入了解。
Syndecans are transmembrane heparan sulfate proteoglycans with roles in cell proliferation, differentiation, adhesion, and migration. They have been associated with multiple functions in tumour progression, through their ability to interact with a wide range of ligands as well as other receptors, which makes them key effectors in the pericellular microenvironment. Extracellular shedding of syndecans by tumour-associated matrix metalloproteinases (MMPs) may have an important role in tumour progression. Such ectodomain shedding generates soluble ectodomains that may function as paracrine or autocrine effectors, or as competitive inhibitors of the intact proteoglycan. Tumour-associated MMPs are shown here to cleave the ectodomains of human syndecan-1 and syndecan-4. Two membrane proximal regions of both syndecan-1 and syndecan-4 are favoured MMP cleavage sites, six and 15 residues from the transmembrane domain. Other sites are 3540 residues C-terminal from the heparan sulfate chain substitution sites in both syndecans. The MT1-MMP cleavage sites in syndecan-1 and syndecan-4 were confirmed by site-directed mutagenesis. These findings provide insights into the characteristics of syndecan shedding.