Pei D, Weiss S J
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0640, USA.
Nature. 1995 May 18;375(6528):244-7. doi: 10.1038/375244a0.
Human stromelysin-3, a new member of the matrix metalloproteinase family, is expressed in tissues undergoing the active remodelling associated with embryonic development, wound healing and tumour invasion. But like all other members of the matrix metalloproteinase gene family, stromelysin-3 is synthesized as an inactive precursor that must be processed to its mature form in order to express enzymic activity. Here we identify stromelysin-3 as the first matrix metalloproteinase to be discovered that can be processed directly to its enzymically active form by an obligate intracellular proteolytic event that occurs within the constitutive secretory pathway. Intracellular activation is regulated by an unusual 10-amino-acid insert sandwiched between the pro- and catalytic-domains of stromelysin-3, which is encrypted with an Arg-X-Arg-X-Lys-Arg recognition motif for the Golgi-associated proteinase, furin, a mammalian homologue of the yeast Kex2 pheromone convertase. A furin-stromelysin-3 processing axis not only differentiates the regulation of this enzyme from all previously characterized matrix metalloproteinases, but also identifies pro-protein convertases as potential targets for therapeutic intervention in matrix-destructive disease states.
人基质溶解素-3是基质金属蛋白酶家族的一个新成员，在与胚胎发育、伤口愈合和肿瘤侵袭相关的活跃重塑组织中表达。但与基质金属蛋白酶基因家族的所有其他成员一样，基质溶解素-3最初是以无活性的前体形式合成的，必须经过加工才能成为成熟形式，从而表现出酶活性。在此，我们确定基质溶解素-3是首个被发现的基质金属蛋白酶，它可通过组成型分泌途径中发生的专一性细胞内蛋白水解事件直接加工成具有酶活性的形式。细胞内激活受夹在基质溶解素-3前结构域和催化结构域之间的一段特殊的10个氨基酸插入序列调控，该序列含有用于高尔基体相关蛋白酶弗林蛋白酶（酵母Kex2信息素转化酶的哺乳动物同源物）的Arg-X-Arg-X-Lys-Arg识别基序。弗林蛋白酶-基质溶解素-3加工轴不仅使该酶的调控与所有先前已表征的基质金属蛋白酶不同，还将前体蛋白转化酶确定为基质破坏性疾病状态下治疗干预的潜在靶点。
