Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation

Signal regulatory proteins of the alpha subtype (SIRP alpha) are ubiquitous molecules of the immunoglobulin superfamily that negatively regulate prote in tyrosine kinase receptor-dependent cell proliferation. Their intracytopl asmic domain contains four motifs that resemble immunoreceptor tyrosine-bas ed 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 SIRP alpha are coexpressed with ITAM-bearing receptors in hematopo ietic cells, we investigated whether SIRP alpha could negatively regulate I TAM-dependent cell activation. We found SIRPa transcripts in human mast cel ls, and we show that a chimeric molecule having the transmembrane and intra cytoplasmic domains of SIRP alpha could inhibit IgE-induced mediator secret ion and cytokine synthesis by mast cells. Inhibition required that the SIRP alpha chimera was coaggregated with ITAM-bearing high affinity IgE recepto rs (Fc epsilon RI). It was correlated with the tyrosyl phosphorylation of t he SIRP alpha chimera and the recruitment of SHP-1 and SHP-2. The phosphory lation of Fc epsilon RI ITAMs was decreased; the mobilization of intracellu lar Ca2+ and the influx of extracellular Ca2+ were reduced, and the activat ion of the mitogen-activated protein kinases Erk1 and Erk2 was abolished. S IRP alpha can therefore negatively regulate not only receptor tyrosine kina se-dependent cell proliferation but also ITAM-dependent cell activation.