Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation.
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.
Liénard
H
H
Laboratoire d'Immunologie Cellulaire et Clinique, INSERM U.255, Institut Curie, 75005 Paris, France.
Bruhns
P
P
Malbec
O
O
Fridman
W H
WH
Daëron
M
M
D000943:Antigens, Differentiation; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules / Q000502:physiology*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
D000943:Antigens, Differentiation; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D017455:Receptors, IgE; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D002118:Calcium