CHYMASE CLEAVAGE OF STEM-CELL FACTOR YIELDS A BIOACTIVE, SOLUBLE PRODUCT

Stem cell factor (SCF) is produced by stromal cells as a membrane-boun d molecule, which may be proteolytically cleaved at a site close to th e membrane to produce a soluble bioactive form. The proteases producin g this cleavage are unknown, In this study, we demonstrate that human mast cell chymase, a chymotrypsin-like protease, cleaves SCF at a nove l site, Cleavage is at the peptide bond between Phe-158 and Met-159, w hich are encoded by exon 6 of the SCF gene, This cleavage results in a soluble bioactive product that is 7 amino acids shorter at the C term inus than previously identified soluble SCF, This research shows the i dentification of a physiologically relevant enzyme that specifically c leaves SCF, Because mast cells express the KIT protein, the receptor f or SCF, and respond to SCF by proliferation and degranulation, this ob servation identifies a possible feedback loop in which chymase release d from mast cell secretory granules may solubilize SCF bound to the me mbrane of surrounding stromal cells, The liberated soluble SCF may in turn stimulate mast cell proliferation and differentiated functions; t his loop could contribute to abnormal accumulations of mast cells in t he skin and hyperpigmentation at sites of chronic cutaneous inflammati on.