Soluble extracellular matrix metalloproteinase inducer (EMMPRIN, EMN) regulates cancer-related cellular functions by homotypic interactions with surface CD147
Soluble extracellular matrix metalloproteinase inducer (EMMPRIN, EMN) regulates cancer-related cellular functions by homotypic interactions with surface CD147
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DOI：
10.1111/febs.13414
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发表时间：
2015-11-01
期刊：
影响因子：
5.4
通讯作者：
Friedrich, Karlheinz
中科院分区：
文献类型：
--
作者：
Knutti, Nadine;Kuepper, Michael;Friedrich, Karlheinz
EMMPRIN(细胞外基质金属蛋白酶诱导物)是一种广泛表达的糖蛋白，是免疫球蛋白超家族的成员，既存在于膜上，也存在于可溶性中。EMMPRIN的同型相互作用奠定了它在正常发育和病理情况下的多种作用，如病毒感染、阿尔茨海默病和癌症。本研究以重组的可溶的、完全糖基化的EMMPRIN结构域(RhsEMN)为工具，研究了EMMPRIN-EMMPRIN受体(EMNR)接触的结构基础及其对MCF-7乳腺癌细胞的作用。RhsEMN在溶液中不形成二聚体，但与MCF-7细胞表面的EMMPRIN(EMN)结合，亲和力高，易于内化。同型接触的相互作用界面定位于N-末端Ig结构域。RhsEMN对MCF-7细胞的增殖有促进作用，但对细胞迁移有抑制作用，且呈剂量依赖性。伴随着这些作用的是内源性EMMPRIN和基质金属蛋白酶-14(MMP-14)的上调，基质金属蛋白酶-14是一种参与细胞外释放可溶性EMMPRIN的膜结合蛋白酶，表明了一种调节反馈机制。一种新的针对EMMPRIN的功能性抗体模拟了rhsEMN的促增殖活性，强调了细胞表面EMMPRIN的交联性(EMNR)在诱导细胞内信号转导中起着关键作用。针对HEK-293细胞中与肿瘤相关的信号转导，我们可以证明rhsEMN触发了致癌的Wnt通路。
EMMPRIN (extracellular matrix metalloproteinase inducer) is a widely expressed glycoprotein and a member of the immunoglobulin superfamily which exists in both a membrane-spanning and a soluble form. Homotypic interactions of EMMPRIN underlie its multiple roles in normal development and pathological situations such as viral infections, Alzheimer's disease and cancer. This study employed a recombinant soluble, fully glycosylated EMMPRIN domain (rhsEMN) as a tool to characterize the structural basis of EMMPRIN-EMMPRIN receptor (EMNR) contacts and their functional effects on MCF-7 breast carcinoma cells. rhsEMN did not form dimers in solution but bound to surface EMMPRIN (EMN) on MCF-7 cells with high affinity and was readily internalized. The interaction interface for the homotypic contact was localized to the N-terminal Ig domain. rhsEMN exerted a stimulatory effect on proliferation of MCF-7 cells whereas it reduced cell migration in a dose-dependent manner. These effects were accompanied by an upregulation of endogenous EMMPRIN as well as of matrix metalloproteinase-14 (MMP-14), a membrane-bound protease involved in the extracellular release of soluble EMMPRIN, indicating a regulatory feedback mechanism. The proliferation-promoting activity of rhsEMN was mimicked by a novel functional antibody directed to EMMPRIN, underscoring that crosslinking of cell surface EMMPRIN (EMNR) is crucial for eliciting intracellular signalling. Addressing malignancy-related signal transduction in HEK-293 cells, we could show that rhsEMN triggers the oncogenic Wnt pathway.