CALMODULIN REGULATES L-SELECTIN ADHESION MOLECULE EXPRESSION AND FUNCTION THROUGH A PROTEASE-DEPENDENT MECHANISM

Expression of the L-selectin adhesion molecule is rapidly down-regulat ed upon cell activation through proteolysis at a membrane-proximal sit e. Here we demonstrate that calmodulin, an intracellular calcium regul atory protein, specifically coprecipitates with L-selectin through a d irect association with the cytoplasmic domain of L-selectin. Furthermo re, calmodulin inhibitors disrupt L-selectin-dependent adhesion by ind ucing proteolytic release of L-selectin from the cell surface. The eff ects of the calmodulin inhibitors on L-selectin expression and functio n can be prevented by cotreatment with a hydroxamic acid-based metallo protease inhibitor. Our results suggest a novel role for calmodulin in regulating the expression and function of an integral membrane protei n through a protease-dependent mechanism. These findings may have broa der implications for other cell surface proteins that also undergo reg ulated proteolysis.