Secretion of Active Membrane Type 1 Matrix Metalloproteinase (MMP-14) Into Extracellular Space in Microvesicular Exosomes
Secretion of Active Membrane Type 1 Matrix Metalloproteinase (MMP-14) Into Extracellular Space in Microvesicular Exosomes
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DOI：
10.1002/jcb.21923
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发表时间：
2008-12-01
影响因子：
4
通讯作者：
Keski-Oja, Jorma
中科院分区：
文献类型：
--
作者：
Hakulinen, Juha;Sankkila, Lotta;Keski-Oja, Jorma
膜型基质金属蛋白酶1(MT1-MMP14)是一种高效的细胞外基质(ECM)降解酶，在组织内稳态和细胞侵袭中发挥重要作用。和许多I型膜蛋白一样，MT1-MMPs可以从细胞表面通过早期和再循环的内小体内化到晚期的内小体，再循环到质膜。晚期内小体参与小囊泡(30-100 nm)的生物发生，外小体将质膜蛋白重新定向到细胞外分泌。我们推测，一些内体MT1-MMPs可能被导向外体以获得细胞外的释放。使用培养的人纤维肉瘤(HT-1080)和黑色素瘤(G361)细胞，我们提供了证据，证明全长60 kDa和经蛋白降解处理的43 kDa形式的MT1-MMP都在外体中分泌。通过电子显微镜下的泡状结构以及胞外体标记蛋白CD9和肿瘤易感基因(TSG101)对分离的胞外体进行鉴定。此外，外切体还含有β1整合素(CD29)。外切体能够激活原-MMP2，降解1型胶原和明胶，提示外切体MT1-MMPs具有功能活性。MT1-MMP靶向外切体是癌细胞分泌膜型金属蛋白水解酶活性进入细胞外间隙的一种新机制。J.细胞。生物化学。105：1211-1218,2008。(C)2008年Wiley-Liss，Inc.
Membrane type 1 matrix metalloproteinase (MT1-MMP, MMP14) is an efficient extracellular matrix (ECM) degrading enzyme that plays important roles in tissue homeostasis and cell invasion. Like a number of type I membrane proteins, MT1-MMP can be internalized from the cell surface through early and recycling endosomes to late endosomes, and recycled to the plasma membrane. Late endosomes participate in the biogenesis of small (30-100 nm) vesicles, exosomes, which redirect plasma membrane proteins for extracellular secretion. We hypothesized that some of the endosomal MT1-MMP could be directed to exosomes for extracellular release. Using cultured human fibrosarcoma (HT-1080) and melanoma (G361) cells we provide evidence that both the full-length 60 kDa and the proteolytically processed 43 kDa forms of MT1-MMP are secreted in exosomes. The isolated exosomes were identified by their vesicular structure in electron microscopy and by exosomal marker proteins CD9 and tumor susceptibility gene (TSG101). Furthermore, exosomes contained beta 1-integrin (CD29). The exosomes were able to activate pro-MMP-2 and degrade type 1 collagen and gelatin, suggesting that the exosomal MT1-MMP was functionally active. The targeting of MT1-MMP in exosomes represents a novel mechanism for cancer cells to secrete membrane type metalloproteolytic activity into the extracellular space. J. Cell. Biochem. 105: 1211-1218, 2008. (c) 2008 Wiley-Liss, Inc.