SELECTIVE PROCESSING OF SUBMANDIBULAR RAT 1 PROTEIN AT DIBASIC CLEAVAGE SITES - SALIVARY AND BLOOD-STREAM SECRETION PRODUCTS

The amino acid sequence of submandibular rat 1 (SMR1) protein, deduced from its cDNA sequence, led to the prediction that the SMR1 gene enco des a hormone-like precursor [Rosinski-Chupin, I., Tronik, D. and Roug eon, E (1988) Proc. Natl Acad. Sci. USA 85, 8553-8557]. SMR1 contains an N-terminal putative secretory signal sequence and a tetrapeptide (Q HNP), located between dibasic amino acids which constitute the most co mmon signal for prohormone processing. We have isolated and characteri zed from the male rat submandibular gland and its secretions three str ucturally related peptides, namely an undecapeptide (VRGPRRQHNPR), a h exapeptide (RQHNPR) and a pentapeptide (QHNPR) generated from SMR1 by selective proteolytic cleavages at pairs of arginine residues. The bio synthesis of these peptides is subjected to distinct regulatory pathwa ys depending on the organ, sex and age of the rat. Furthermore, the pe ptides are differentially distributed in the submandibular gland and i n resting or epinephrine-elicited submandibular salivary secretions, s uggesting distinct proteolytic pathways for their maturation. The unde capeptide is generated in the gland of both male and female rats, but under basal conditions it is only released into the saliva in male ani mals. The hexapeptide is produced in large amounts in the gland of adu lt male rats and released into the saliva in both resting and stimulat ed conditions. The pentapeptide appears only in the male saliva and is present mostly under stimulated conditions. In addition, administrati on of epinephrine induces the release of the hexapeptide from the subm andibular gland into the bloodstream. The evidence indicates that the rat submandibular gland can function as a dual exocrine and endocrine organ for the SMR1-derived hexapeptide, as has been reported for nerve growth factor, epidermal growth factor, renin and kallikrein. Althoug h the biological activities of the SMR1-derived peptides are not yet k nown, their high production and adrenergic-induced release only into t he saliva and bloodstream of adult male rats, suggest a physiological involvement in some male-specific processes.