Flowing leukocytes use the glycoprotein PSGL-1 to tether to and roll on P-selectin on activated endothelial cells and platelets. These two proteins are a novel prototype for a lectin-glycoprotein interaction that mediates cell adhesion and signaling. The investigator and coworkers have obtained preliminary data suggesting that P-selectin and PSGL-1 dimerize in the membrane and interact with cytoplasmic proteins. They hypothesize that the transmembrane and cytoplasmic domains mediate these interactions, which in turn regulate the cell surface distributions, adhesive functions, and signaling capabilities of P-selectin and PSGL-1. There are five specific aims: 1) determine whether the cytoplasmic domain of P-selectin regulates its cell surface distribution and its adhesive function, 2) determine whether P-selectin dimerizes in the membrane, and if so, whether dimerization affects its adhesive function or internalization efficiency, 3) determine whether the cytoplasmic or transmembrane domain of PSGL-1 regulates its dimerization, cell surface distribution, or adhesive function, 4) identify proteins that are phosphorylated upon PSGL-1 engagement and determine whether the transmembrane and cytoplasmic domains of PSGL-1 are required for signaling, and 5) characterize proteins that bind to the cytoplasmic domains of PSGL-1.
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