Khayati Farah, Pérez-Cano Laura, Maouche Kamel, Sadoux Aurélie, Boutalbi Zineb, Podgorniak Marie-Pierre, Maskos Uwe, Setterblad Niclas, Janin Anne, Calvo Fabien, Lebbé Céleste, Menashi Suzanne, Fernandez-Recio Juan, Mourah Samia
INSERM UMR-S 976, Hôpital Saint-Louis, Paris, France.
Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
Oncotarget. 2015;6(12):9766-80. doi: 10.18632/oncotarget.2870.
EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated. This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo. Computational docking analyses and mutagenesis studies identified a molecular binding site in the extracellular domain of EMMPRIN located close to the cell membrane and containing the amino acids 195/199. EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.
细胞外基质金属蛋白酶诱导因子/CD147主要因其诱导蛋白酶的功能而为人所知，但它在促进肿瘤血管生成中的作用也已得到证实。本研究提供了证据，表明细胞外基质金属蛋白酶诱导因子在内皮细胞和肿瘤细胞中都是血管内皮生长因子受体-2（VEGFR-2）酪氨酸激酶受体的新共受体，因为它直接与之相互作用，并在体外和体内调节其被血管内皮生长因子（VEGF）配体激活的过程、信号传导及功能后果。计算机对接分析和诱变研究确定了细胞外基质金属蛋白酶诱导因子胞外结构域中靠近细胞膜且包含第195/199位氨基酸的一个分子结合位点。细胞外基质金属蛋白酶诱导因子在癌症中过表达，因此能够进一步增强VEGFR-2的激活，这表明抗血管生成药物与细胞外基质金属蛋白酶诱导因子/VEGFR-2相互作用抑制剂的联合治疗可能对抑制血管生成和恶性肿瘤有更大影响。
