Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
Biochem Biophys Res Commun. 2011 Sep 23;413(2):277-81. doi: 10.1016/j.bbrc.2011.08.085. Epub 2011 Aug 27.
MT1-MMP/MMP-14 is a major invasion-promoting membrane protease expressed in macrophages. In addition to its proteolytic activity that degrades the extracellular matrix, MT1-MMP also boosts ATP production in cells in a manner independent of its proteolytic activity. It remains unclear to what extent the proteolytic and energy-boosting activities of MT1-MMP contribute to macrophage invasion. Recently, we demonstrated that the cytoplasmic tail of MT1-MMP makes use of APBA3/Mint3 to activate HIF-1 and thereby boosts glycolysis for ATP production. Here, we used Apba3(-/-) macrophages to dissect the contribution of the proteolytic and the energy-boosting activities of MT1-MMP. The proteolytic activity of MT1-MMP was not affected by the lack of APBA3 in macrophages. Apba3(-/-) and Mmp14(-/-) macrophages exhibited a 55% reduction of ATP levels compared to wild-type (WT) cells and the rate of motility of the mutant cells was accordingly reduced. In contrast, matrigel invasion by Mmp14(-/-) and Apba3(-/-) macrophages was reduced to 24% and 55.4%, respectively, of the level observed in WT cells. These results represent the first attempt to dissect the contribution of the two invasion-promoting activities of MT1-MMP to macrophage invasion.
MT1-MMP/MMP-14 是一种主要的侵袭促进型膜蛋白酶，在巨噬细胞中表达。除了具有降解细胞外基质的蛋白水解活性外，MT1-MMP 还能以独立于其蛋白水解活性的方式促进细胞内的 ATP 产生。目前尚不清楚 MT1-MMP 的蛋白水解和能量增强活性在多大程度上促进了巨噬细胞的侵袭。最近，我们证明了 MT1-MMP 的细胞质尾巴利用 APBA3/Mint3 来激活 HIF-1，从而促进糖酵解产生 ATP。在这里，我们使用 Apba3(-/-)巨噬细胞来剖析 MT1-MMP 的蛋白水解和能量增强活性的贡献。APBA3 在巨噬细胞中的缺失并不影响 MT1-MMP 的蛋白水解活性。与野生型 (WT) 细胞相比，Apba3(-/-)和 Mmp14(-/-)巨噬细胞的 ATP 水平降低了 55%，因此其运动速度相应降低。相比之下，Mmp14(-/-)和 Apba3(-/-)巨噬细胞的基质胶侵袭能力分别降低至 WT 细胞水平的 24%和 55.4%。这些结果代表了首次尝试剖析 MT1-MMP 的两种促进侵袭的活性对巨噬细胞侵袭的贡献。
