Calmodulin regulates L-selectin adhesion molecule expression and function through a protease-dependent mechanism.
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.
Kahn
J
J
Boehringer Ingelheim Pharmaceuticals, Inc., Department of Immunological Diseases, Ridgefield, Connecticut 06877, USA.
Walcheck
B
B
Migaki
G I
GI
Jutila
M A
MA
Kishimoto
T K
TK
D000595:Amino Acid Sequence; D002147:Calmodulin / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D019041:L-Selectin / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D008198:Lymph Nodes / Q000737:chemistry / Q000201:enzymology; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D018492:Dopamine Antagonists; D019041:L-Selectin; D014268:Trifluoperazine; D010450:Endopeptidases