A new physiologic function of tissue kallikrein family enzymes and processing of growth factor precursors

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1. Four tissue kallikrein family enzymes (mK1, mK9, mK13, mK22) were prepared from mouse submandibular gland. mK13 was ientified to be a prorenin converting enzyme. mK9, a binding protein for EGF,was found to have an activity to hydrolyze prorenin to give an active renin. Acting on prorenin, mK22 (beta-NGF endopeptidase) gave two products renin and arginyl renin. On the other hand, mK1, a true kallikrein did not process renin at all. The results suggest that tissue kallikrein family enzyme bearing higher kinin-releasing activity have lower prorenin-converting activity and vice versa. These enzymes may possibly have a physiologic role in the tissue rein-angiotensin system2. From the submandibular gland of DBA/2N mice, and enzyme of tissue kallikrein family was purified and sequenced. A cDNA of this enzyme was also cloned and nucleotide sequence was determined. The enzyme was highly homologous to mK13/mK26, a prorenin converting enzyme (PRECE). It actually had the activity to give renin from its precursor prorenin. The presence and absence of the present enzyme and mK13/mK26 in DBA/2N and ICR mice suggested that the purified enzyme is an allozyme of PRECE (PRECE^b).3. Anti-mK1 antiserum specific to, its antigen was prepared by absorption of antiserum with purified tissue kallikrein enzymes. Immunohistochemical localization of mK1 was then invetigated using the specific antiserum. mK1 localized in the secretory granules of segregated number of granular convoluted tublar cells (GCT cellls). Such mosaic staining pattern was seen in both males and females. The cell type that shows possitive reaction was different between males and females ; slender GCT cells were stained in males whereas typical pyramydal cells were stained in females. About 5% of GCT cells in males were immunoreactive for mK1, whereas 65% of these segments were positive in females.