Abstract

Signal regulatory proteins of the alpha subtype (SIRPalpha) 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 SIRPalpha are coexpressed with ITAM-bearing receptors in hematopoietic cells, we investigated whether SIRPalpha could negatively regulate ITAM-dependent cell activation. We found SIRPalpha transcripts in human mast cells, and we show that a chimeric molecule having the transmembrane and intracytoplasmic domains of SIRPalpha could inhibit IgE-induced mediator secretion and cytokine synthesis by mast cells. Inhibition required that the SIRPalpha chimera was coaggregated with ITAM-bearing high affinity IgE receptors (FcepsilonRI). It was correlated with the tyrosyl phosphorylation of the SIRPalpha chimera and the recruitment of SHP-1 and SHP-2. The phosphorylation of FcepsilonRI ITAMs was decreased; the mobilization of intracellular Ca(2+) and the influx of extracellular Ca(2+) were reduced, and the activation of the mitogen-activated protein kinases Erk1 and Erk2 was abolished. SIRPalpha can therefore negatively regulate not only receptor tyrosine kinase-dependent cell proliferation but also ITAM-dependent cell activation.

Highlights

  • Tel.: 33-1-4432-4223; Fax: 33-14051-0420; E-mail: Marc.Daeron@curie.fr. 1 The abbreviations used are: BIT, brain immunoglobulin-like molecule with tyrosine-based activation motifs; Fc⑀RI, high affinity IgE receptors; Fc␥RIIB and Fc␥RIIIA, low affinity IgG Receptors; goat antimouse Ig (GAM), goat anti-mouse Ig; GAR, goat anti-rabbit Ig; Horseradish peroxidase (HRP), horseradish peroxidase; IC, intracytoplasmic; immunoreceptor tyrosine-based activation motifs (ITAMs), immunoreceptor tyrosine-based activation motif; inhibition motifs (ITIMs), immunoreceptor tyrosine-based inhibition motif; KIRs, killer cell inhibitory receptors; MAR, mouse anti-rat Ig; RTK, receptor tyrosine kinase; SH2, Src homology domain 2; SHIP, SH2 domain-bearing inositol-phosphate phosphatase; SHP, SH2 domainbearing protein tyrosine phosphatase; SHP substrate 1 (SHPS-1), SH2 domain-bearing phosphatase substrate 1; SIRPs, signal regulatory proteins; TNP, trinitrophenyl; MAP, mitogen-activated protein; DNP, 2,4-dinitrophenol; phoproteins that coprecipitated with SH2 domain-bearing protein tyrosine phosphatases (SHPs) [1,2,3]

  • ITIMs are present in a large group of molecules [7] that negatively regulate cell activation induced by receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs) [8]

  • A SIRP␣ Chimera Inhibits IgE-induced Mast Cell Activation When Coligated with Fc⑀RI—In order to examine whether SIRP␣ could inhibit IgE-induced mast cell activation, we constructed a cDNA encoding a chimeric molecule having the extracellular domain of murine Fc␥RIIB and the TM and IC domains of human SIRP␣ (Fc␥RIIB-SIRP␣)

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Summary

Introduction

Phoproteins that coprecipitated with SH2 domain-bearing protein tyrosine phosphatases (SHPs) [1,2,3]. We report here that, when coaggregated with Fc⑀RI, a chimeric molecule whose IC domain was that of human SIRP␣ could inhibit IgE-induced mediator release and cytokine secretion by mast cells.

Results
Conclusion

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