Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration.
Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration.
复制标题
膜型1基质金属蛋白酶切割CD44并促进细胞迁移。
DOI：
10.1083/jcb.153.5.893
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发表时间：
2001-05-28
影响因子：
7.8
通讯作者：
Seiki, M
中科院分区：
文献类型：
--
作者：
Kajita, M;Itoh, Y;Chiba, T;Mori, H;Okada, A;Kinoh, H;Seiki, M
包括侵袭性肿瘤细胞在内的迁移细胞经常表达 CD44，这是透明质酸和膜 1 型基质金属蛋白酶 (MT1-MMP) 的主要受体，可降解细胞周围区域的细胞外基质。在这项研究中，我们证明 MT1-MMP 作为 CD44H 的加工酶，将其作为可溶性 70 kD 片段释放到培养基中。此外，这种加工过程会刺激细胞运动；然而，单独表达 CD44H 或 MT1-MMP 并不能刺激细胞运动。 MT1-MMP 和缺乏 MT1-MMP 加工位点的突变 CD44H 的共表达不会导致脱落，也不会促进细胞迁移，表明 MT1-MMP 对 CD44H 的加工在迁移刺激中至关重要。此外，突变体CD44H的表达以显性失活的方式抑制CD44H和MT1-MMP促进的细胞迁移。胰腺肿瘤细胞系 MIA PaCa-2 被发现以 MT1-MMP 依赖性方式脱落 70-kD CD44H 片段。细胞中突变型 CD44H 的表达以及 MMP 抑制剂处理有效抑制了迁移，表明 MIA PaCa-2 细胞确实使用 CD44H 和 MT1-MMP 作为迁移装置。这些发现揭示了两种分子之间的新相互作用，这两种分子均与肿瘤细胞迁移和侵袭有关。
Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP–processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP–dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion.