Signal Regulatory Proteins Negatively Regulate Immunoreceptor-dependent Cell Activation

Signal regulatory proteins of the α subtype (SIRPα) are ubiquitous molecules of the immunoglobulin superfamily that negatively regulate protein tyrosine kinase receptor-dependent cell proliferation. Their intracytoplasmic domain contains four motifs that resemble immunoreceptor tyrosine-based inhibition motifs (ITIMs) and that, when tyrosyl-phosphorylated, recruit cytoplasmic SH2 domain-bearing protein tyrosine phosphatases (SHPs). ITIMs are borne by molecules that negatively regulate cell activation induced by receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs). Because SIRPα are coexpressed with ITAM-bearing receptors in hematopoietic cells, we investigated whether SIRPα could negatively regulate ITAM-dependent cell activation. We found SIRPα transcripts in human mast cells, and we show that a chimeric molecule having the transmembrane and intracytoplasmic domains of SIRPα could inhibit IgE-induced mediator secretion and cytokine synthesis by mast cells. Inhibition required that the SIRPα chimera was coaggregated with ITAM-bearing high affinity IgE receptors (FcεRI). It was correlated with the tyrosyl phosphorylation of the SIRPα chimera and the recruitment of SHP-1 and SHP-2. The phosphorylation of FcεRI ITAMs was decreased; the mobilization of intracellular Ca2+and the influx of extracellular Ca2+ were reduced, and the activation of the mitogen-activated protein kinases Erk1 and Erk2 was abolished. SIRPα can therefore negatively regulate not only receptor tyrosine kinase-dependent cell proliferation but also ITAM-dependent cell activation.