Chymase cleavage of stem cell factor yields a bioactive, soluble product
Chymase cleavage of stem cell factor yields a bioactive, soluble product
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DOI：
10.1073/pnas.94.17.9017
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发表时间：
1997-08-19
影响因子：
11.1
通讯作者：
Schechter, NM
中科院分区：
文献类型：
--
作者：
Longley, BJ;Tyrrell, L;Schechter, NM
干细胞因子 (SCF) 由基质细胞产生，作为膜结合分子，可以在靠近膜的位点进行蛋白水解，产生可溶性生物活性形式。产生这种裂解的蛋白酶尚不清楚，在这项研究中，我们证明人类肥大细胞糜蛋白酶（一种胰凝乳蛋白酶样蛋白酶）在一个新位点裂解 SCF，裂解位于 Phe-158 和 Met-159 之间的肽键处，由 SCF 基因的外显子 6 编码。这种裂解产生可溶性生物活性产物，其 C 端比以前短 7 个氨基酸鉴定出可溶性 SCF，这项研究表明鉴定出一种特异性裂解 SCF 的生理相关酶，因为肥大细胞表达 KIT 蛋白（SCF 的受体），并通过增殖和脱粒对 SCF 做出反应，这一观察结果确定了一个可能的反馈回路，其中从肥大细胞分泌颗粒释放的食糜酶可以溶解与周围基质细胞膜结合的 SCF，释放的可溶性 SCF 可能反过来刺激肥大细胞增殖和分化功能；该循环可能导致皮肤中肥大细胞的异常积累以及慢性皮肤炎症部位的色素沉着过度。
Stem cell factor (SCF) is produced by stromal cells as a membrane-bound molecule, which may be proteolytically cleaved at a site close to the membrane to produce a soluble bioactive form. The proteases producing this cleavage are unknown, In this study, we demonstrate that human mast cell chymase, a chymotrypsin-like protease, cleaves SCF at a novel site, Cleavage is at the peptide bond between Phe-158 and Met-159, which 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 terminus than previously identified soluble SCF, This research shows the identification of a physiologically relevant enzyme that specifically cleaves SCF, Because mast cells express the KIT protein, the receptor for SCF, and respond to SCF by proliferation and degranulation, this observation identifies a possible feedback loop in which chymase released from mast cell secretory granules may solubilize SCF bound to the membrane of surrounding stromal cells, The liberated soluble SCF may in turn stimulate mast cell proliferation and differentiated functions; this loop could contribute to abnormal accumulations of mast cells in the skin and hyperpigmentation at sites of chronic cutaneous inflammation.