The sialoadhesin CD33 is a myeloid-specific inhibitory receptor

Activating and inhibitory receptors act in concert to regulate cellular act ivation. Inhibitory receptors are characterized by the presence of a charac teristic sequence known as an immunoreceptor tyrosine-based inhibitory moti f (ITIM) in their cytoplasmic tail. Phosphorylated ITIM serve as docking si tes for the SH2-containing phosphatases which then inhibit signal transduct ion. CD33 is a member of the immunoglobulin superfamily and contains two im munoglobulin-like domains, a transmembrane region and a cytoplasmic tail th at has two potential ITIM sequences. CD33 expression is restricted to cells of myelomonocytic lineage. The precise function of CD33 is unknown althoug h it is a lectin that binds sialic acid residues in N- and O-glycans on cel l surfaces. Co-immunoprecipitation studies demonstrate that CD33 associates with the SH2-containing tyrosine phosphatase SHP-1 in monocytes. The proxi mal ITIM is necessary and sufficient for SHP-1 binding which is mediated by the aminoterminal SH2 domain. Treatment of SHP-1 with a phosphopeptide rep resenting the proximal CD33 ITIM results in increased SHP-1 enzymatic activ ity. CD33 exerts an inhibitory effect on tyrosine phosphorylation and Ca2mobilization when cc-engaged with the activating Fc gamma RI receptor. This data indicates that CD33 is an inhibitory receptor that may regulate Fc ga mma RI signal transduction.