Patel Y C, Galanopoulou A
Fraser Laboratories, Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.
Ciba Found Symp. 1995;190:26-40; discussion 40-50. doi: 10.1002/9780470514733.ch3.
Prosomatostatin is cleaved at dibasic and monobasic sites to produce somatostatin-14 and somatostatin-28 respectively. The mammalian pro-protein convertases comprising furin, PACE4 and PC1-6 have recently been identified and are believed to mediate endoproteolysis of prohormone precursors such as prosomatostatin. Furin is membrane bound, localized to the Golgi and mediates constitutive processing. PC1 and PC2 are soluble and are expressed solely in endocrine and neuroendocrine tissues suggesting a key role in prohormone processing. We have investigated the endogenous and heterologous synthesis and processing of rat prosomatostatin in 1027B2 rat islet somatostatinoma cells and in constitutive (COS-7, PC-12) and regulated (AtT-20, GH3/GH4C1) secretory cells. We have correlated processing efficiency with: secretion through the constitutive or regulated pathways; endogenous expression of furin, PC1 and PC2; and expression or overexpression of furin, PC1 and PC2. Pulse-chase studies showed that prosomatostatin is rapidly and independently processed to somatostatin-14 and somatostatin-28. Furin is capable of monobasic processing of prosomatostatin and is a candidate somatostatin-28 convertase. PC1 and PC2 both effect dibasic processing of prosomatostatin and qualify as putative somatostatin-14 convertases. PC1 is active in constitutive and regulated secretory cells, has a broader specificity and is overall more potent than PC2. Efficient processing of prosomatostatin begins in a Golgi or pre Golgi compartment. It requires the milieu of the secretory cell but not the secretory granule.
前生长抑素在双碱性和单碱性位点被切割，分别产生生长抑素-14和生长抑素-28。最近已鉴定出包括弗林蛋白酶、PACE4和PC1-6在内的哺乳动物前体蛋白转化酶，它们被认为介导前激素前体如前生长抑素的内蛋白水解作用。弗林蛋白酶是膜结合的，定位于高尔基体并介导组成型加工。PC1和PC2是可溶性的，仅在内分泌和神经内分泌组织中表达，表明它们在前激素加工中起关键作用。我们研究了大鼠前生长抑素在1027B2大鼠胰岛生长抑素瘤细胞以及组成型（COS-7、PC-12）和调节型（AtT-20、GH3/GH4C1）分泌细胞中的内源性和异源合成及加工过程。我们将加工效率与以下因素相关联：通过组成型或调节型途径的分泌；弗林蛋白酶、PC1和PC2的内源性表达；以及弗林蛋白酶、PC1和PC2的表达或过表达。脉冲追踪研究表明，前生长抑素能迅速且独立地加工成生长抑素-14和生长抑素-28。弗林蛋白酶能够对前生长抑素进行单碱性加工，是生长抑素-28转化酶的候选者。PC1和PC2都能对前生长抑素进行双碱性加工，有资格作为假定的生长抑素-14转化酶。PC1在组成型和调节型分泌细胞中均有活性，具有更广泛的特异性，总体上比PC2更有效。前生长抑素的高效加工始于高尔基体或前高尔基体区室。这需要分泌细胞的环境，但不需要分泌颗粒。
