Kahn J, Walcheck B, Migaki G I, Jutila M A, Kishimoto T K
Boehringer Ingelheim Pharmaceuticals, Inc., Department of Immunological Diseases, Ridgefield, Connecticut 06877, USA.
Cell. 1998 Mar 20;92(6):809-18. doi: 10.1016/s0092-8674(00)81408-7.
Expression of the L-selectin adhesion molecule is rapidly down-regulated upon cell activation through proteolysis at a membrane-proximal site. Here we demonstrate that calmodulin, an intracellular calcium regulatory protein, specifically coprecipitates with L-selectin through a direct association with the cytoplasmic domain of L-selectin. Furthermore, calmodulin inhibitors disrupt L-selectin-dependent adhesion by inducing proteolytic release of L-selectin from the cell surface. The effects of the calmodulin inhibitors on L-selectin expression and function can be prevented by cotreatment with a hydroxamic acid-based metalloprotease inhibitor. Our results suggest a novel role for calmodulin in regulating the expression and function of an integral membrane protein through a protease-dependent mechanism. These findings may have broader implications for other cell surface proteins that also undergo regulated proteolysis.
L-选择素黏附分子的表达在细胞通过膜近端位点的蛋白水解作用被激活后会迅速下调。在此我们证明，钙调蛋白，一种细胞内钙调节蛋白，通过与L-选择素的细胞质结构域直接结合而与L-选择素特异性共沉淀。此外，钙调蛋白抑制剂通过诱导L-选择素从细胞表面的蛋白水解释放来破坏L-选择素依赖性黏附。钙调蛋白抑制剂对L-选择素表达和功能的影响可通过与基于异羟肟酸的金属蛋白酶抑制剂共同处理来预防。我们的结果表明钙调蛋白在通过蛋白酶依赖性机制调节整合膜蛋白的表达和功能方面具有新作用。这些发现可能对其他也经历调节性蛋白水解的细胞表面蛋白具有更广泛的意义。
