MT1-MMP mediates MUM shedding independent of TACE/ADAM17
MT1-MMP mediates MUM shedding independent of TACE/ADAM17
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DOI：
10.1042/bj20040513
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发表时间：
2004-08-15
影响因子：
4.1
通讯作者：
Carson, DD
中科院分区：
文献类型：
--
作者：
Thathiah, A;Carson, DD
MUC 1是一种跨膜粘蛋白，在胚胎着床、保护粘膜上皮免受微生物和酶的攻击以及肿瘤进展的各个方面起着关键作用。在某些物种中，子宫上皮MUC 1蛋白和mRNA表达的减少伴随着胚胎着床。在其他物种中，如兔子和人类，MUC 1似乎在胚泡附着位点被局部去除，这表明蛋白酶的作用。我们以前证明MUC 1是从人子宫上皮细胞系HES的表面蛋白水解释放的，并鉴定为TACE/ADAM 17。（其中TACE代表道岔坏死因子-α转化酶，ADAM代表A去整合素和金属蛋白酶样）作为组成型和PMA刺激的MUC 1脱落酶[Thathiah，Blobel和卡森（2003）J.Biol.Chem.274，3386-3394]。介导MUC 1释放的蛋白水解活性的进一步表征表明，MUC 1脱落也被酪氨酸磷酸酶抑制剂过钒酸盐加速。过钒酸盐而非PMA刺激TACE缺陷细胞中的MUC 1脱落，表明不同于TACE的金属蛋白水解活性的激活。过钒酸盐刺激的MUC 1释放受到TIMP-2（金属蛋白酶组织抑制剂-2）和TIMP-3的抑制，但不受TIMP-1的影响，与MT-MMP（膜型基质金属蛋白酶）一致。MUC 1转染的MT 1-MMP缺陷型成纤维细胞中不存在MUC 1脱落的过钒酸盐刺激，但在MUC 1和MT 1-MMP共转染后恢复。此外，在HES细胞中MT 1-MMP的过表达增强了过钒酸盐刺激的MUC 1释放，并且MT 1-MMP与MUC 1在体内共定位于受体期人子宫上皮的顶端表面。总之，这些研究表征了除了TACE之外的MUC 1脱落酶活性，并将MT 1-MMP鉴定为过钒酸盐刺激的MUC 1脱落酶。
MUC1, a transmembrane mucin, plays a critical role in embryo implantation, protection of mucosal epithelia from microbial and enzymic attack and various aspects of tumour progression. In some species, a decrease in uterine epithelial MUC1 protein and mRNA expression accompanies embryo implantation. In other species, such as rabbits and humans, MUC1 appears to be locally removed at blastocyst attachment sites, suggesting the action of a protease. We previously demonstrated that MUC1 is proteolytically released from the surface of a human uterine epithelial cell line, HES, and identified TACE/ADAM17 (where TACE stands for turnout necrosis factor-a converting enzyme and ADAM for A Disintegrin And Metalloprotease-like) as a constitutive and PMA-stimulated MUC1 sheddase [Thathiah, Blobel and Carson (2003) J. Biol. Chem. 274, 3386-3394]. Further characterization of the proteolytic activity(ies) mediating MUC1 release indicates that MUC1 shedding is also accelerated by the tyrosine phosphatase inhibitor pervanadate. Pervanadate, but not PMA, stimulates MUC1 shedding in TACE-deficient cells, indicating activation of a metalloproteolytic activity(ies) distinct from TACE. Pervanadate-stimulated MUC1 release is inhibited by the TIMP-2 (tissue inhibitor of metalloprotease-2) and TIMP-3, but is unaffected by TIMP-1, consistent with the MT-MMPs (membrane-type matrix metalloproteases). Pervanadate stimulation of MUC1 shedding is absent from MUC1-transfected MT1-MMP-deficient fibroblasts, but is restored after MUC1 and MT1-MMP co-transfection. Furthermore, overexpression of MT1-MMP in HES cells enhances pervanadate-stimulated MUC1 release, and MT1-MMP co-localizes with MUC1 in vivo at the apical surface of receptive-phase human uterine epithelia. Taken together, these studies characterize a MUC1 sheddase activity in addition to TACE and identify MT1-MMP as a pervanadate-stimulated MUC1 sheddase.