Salivary gland development: its mediation by a subtilisin-like proprotein convertase, PACE4.
Salivary gland development: its mediation by a subtilisin-like proprotein convertase, PACE4.
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唾液腺发育：由枯草杆菌蛋白酶样前蛋白转化酶 PACE4 介导。
DOI：
10.2152/jmi.56.241
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
K. Hosoi
中科院分区：
文献类型：
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作者：
T. Akamatsu;A. Azlina;Purevjav Javkhlan;T. Hasegawa;C. Yao;K. Hosoi
下颌下腺是在上皮-间充质相互作用下发育的。其过程受多种生长/分化因子的调节，这些生长/分化因子作为无活性的前体被合成，并通过其多个碱性氨基酸位点（如Arg-X-Lys/Arg-Arg）的有限蛋白水解而被激活。虽然这些加工步骤中的许多被阐明为由枯草杆菌蛋白酶样前蛋白转化酶（SPC）催化，但对SPC在SMG发展中的作用知之甚少。本文主要研究SPC家族成员PACE 4（SPC 4）在SMG发育中的生理作用。在大鼠胚胎SMG（E15）的器官培养系统中，Dec-RVKR-CMK，一种有效的SPC抑制剂，抑制唾液分支和外分泌腺型水通道AQP 5的表达。然而，其他肽基-CMK和胰蛋白酶样丝氨酸蛋白酶抑制剂，包括亮抑酶肽，不影响唾液分支和AQP 5的表达。Dec-RVKR-CMK还抑制了PACE 4的表达，但不抑制该家族的另一个成员弗林蛋白酶的表达。PACE 4催化结构域的特异性抗体抑制唾液分支和AQP 5表达相似。Dec-RVKR-CMK的这些抑制作用通过添加重组BMP 2而部分挽救，所述重组BMP 2的前体是PACE 4的生理底物的候选物。此外，通过其特异性siRNA的PACE 4的转录沉默导致本器官培养系统中唾液分支和AQP 5表达的抑制。这些观察结果强烈支持PACE 4介导SMG发育的观点。
The submandibular gland (SMG) develops under the epithelial-mesenchymal interaction. Its process is regulated by various growth/differentiation factors, which are synthesized as inactive precursors and activated via the limited proteolysis at their multi basic amino acid site(s) such as Arg-X-Lys/Arg-Arg. Although many of these processing steps are elucidated to be catalyzed by subtilisin-like proprotein convertases (SPCs), little is known about the role of SPCs in the SMG development. Here, we focused upon the physiological role of PACE4 (SPC4), a member of SPC family, in the SMG development. In the organ culture system of rat embryonic SMG (E15), Dec-RVKR-CMK, a potent inhibitor for SPCs, inhibited the salivary branching and the expression of an exocrine gland type water channel, AQP5. However, other peptidyl-CMKs and inhibitors for trypsin-like serine proteases including leupeptin did not affect the salivary branching and AQP5 expression. Dec-RVKR-CMK also suppressed the expression of PACE4, but not furin, another member of the family. The specific antibody for the catalytic domain of PACE4 suppressed the salivary branching and AQP5 expression similarly. These inhibitory effects of Dec-RVKR-CMK were partially rescued by the addition of recombinant BMP2 whose precursor is a candidate for the physiological substrates of PACE4. Further, the transcriptional silencing of PACE4 by its specific siRNAs caused the suppression of both the salivary branching and AQP5 expression in the present organ culture system. These observations strongly support the idea that PACE4 mediates the SMG development.