P-selectin glycoprotein ligand 1 (PSGL-1) is a leukocyte adhesion molecule involved in cell tether and rolling on activated endothelium. Our work shows that PSGL-1 associates with Syk. This association is mediated by the actin-linking proteins moesin and ezrin, which directly interact with Syk in an ITAM-dependent manner. PSGL-1 engagement induces tyrosine phosphorylation of Syk and SRE-dependent transcriptional activity. Treatment of cells with the Syk inhibitor piceatannol and overexpression of either a Syk dead kinase mutant or an ITAM-mutated moesin abrogated PSGL-1-induced transcriptional activation. These data unveil a new functional role for the ERMs (ezrin/radixin/moesin) as adaptor molecules in the interactions of adhesion receptors and intracellular tyrosine kinases and show that PSGL-1 is a signaling molecule in leukocytes.