Nachtigal M W, Ingraham H A
Department of Physiology, Program in Developmental Biology, University of California, San Francisco 94143-0444, USA.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7711-6. doi: 10.1073/pnas.93.15.7711.
During male gonadal development Müllerian duct regression is mediated by the actions of the hormone Müllerian inhibiting substance (MIS), a member of the transforming growth factor beta superfamily. MIS is considered to be unique among members of this superfamily because bioactivation of MIS via proteolytic processing is hypothesized to occur at its target organ, the Müllerian duct. We find instead that the majority of MIS is processed and secreted from the embryonic testes as a complex in which the mature region remains noncovalently associated with the prodomain. In addition, we have identified two candidate endoproteases that are expressed in the testes and that may be capable of processing MIS in vivo. These kex2/subtilisin-like enzymes, PC5 and furin, are members of the proprotein convertase family that have been implicated in hormone bioactivation via proteolytic processing after dibasic amino acid cleavage recognition sites. Coexpression of PC5 and MIS in transfected mammalian cells results in efficient processing and bioactivation of MIS. Our results suggest that MIS is a natural substrate for PC5, thereby supporting a role for prohormone convertases in the activation of transforming growth factor beta-related hormones during development.
在雄性性腺发育过程中，苗勒管退化是由苗勒管抑制物质（MIS）介导的，MIS是转化生长因子β超家族的成员之一。MIS被认为在该超家族成员中是独特的，因为据推测，MIS通过蛋白水解加工的生物活化发生在其靶器官——苗勒管。相反，我们发现大多数MIS作为一种复合物从胚胎睾丸中加工并分泌出来，其中成熟区域与前结构域保持非共价结合。此外，我们鉴定出两种在睾丸中表达的候选内切蛋白酶，它们可能能够在体内加工MIS。这些类kex2/枯草杆菌蛋白酶的酶，即PC5和弗林蛋白酶，是前蛋白转化酶家族的成员，它们通过在双碱性氨基酸切割识别位点后的蛋白水解加工参与激素生物活化。在转染的哺乳动物细胞中共表达PC5和MIS会导致MIS的有效加工和生物活化。我们的结果表明，MIS是PC5的天然底物，从而支持前激素转化酶在发育过程中对转化生长因子β相关激素的激活作用。
