Physiological Role of a Subtilisin-like Proprotein Convertase, PACE4,in Submandibular Gland Development

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  • Akamatsu Tetsuya
    Department of Molecular Oral Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School

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The submandibular gland (SMG), like teeth and other glandular tissues, develops under epithelial-mesenchymal interaction. Its process is regulated by various signaling molecules, including growth/differentiation factors, which are synthesized as inactive precursors and activated via limited proteolysis. At their processing site, multi-basic amino acid sequences, such as Arg-X-Lys/Arg/X-Arg, commonly exist. It is revealed that subtilisin-like proprotein convertases (SPCs) catalyze such processing; however, little is known about the role of SPCs in SMG development. This study therefore focused on the physiological role of an SPC member, PACE4 (SPC4), in SMG development. In the organ culture system of rat embryonic SMG rudiments, decanoyl-Arg-Val-Lys-Arg-chloromethylketone (Dec-RVKR-CMK), a potent inhibitor of SPCs, inhibited the branching morphogenesis (BM) of SMG and the expression of AQP5, an exocrine-type water channel. In contrast, other inhibitors of trypsin-like serine proteases, including leupeptin and other peptidyl-CMKs, affected neither BM nor AQP5 expression. Dec-RVKR-CMK also suppressed the expression of PACE4, but not another SPC, furin. Additionally, the PACE4-specific antibody suppressed BM and AQP5 expression similarly. A rescue experiment to find the key molecule, which was recovered from Dec-RVKR-CMK-induced suppression of BM and AQP5 expression, revealed that signaling by BMP2, whose precursor is a candidate physiological substrate of PACE4, is involved in the BM and AQP5 expression. Further, the transcriptional silencing of PACE4 by PACE4-specific siRNAs caused the suppression of BM and AQP5 expression in the present organ culture system. These observations strongly suggest that PACE4 plays an important role in SMG development.

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