Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family.
Two closely related proteins, signal regulatory protein alpha (SIRPalpha; SHPS-1/CD172) and SIRPbeta, have been described in humans. The existence of a third SIRP protein has been suggested by cDNA sequence only. We show that this third SIRP is a separate gene that is expressed as a protein with unique characteristics from both alpha and beta genes and suggest that this gene should be termed SIRPgamma. We have expressed the extracellular region of SIRPgamma as a soluble protein and have shown that, like SIRPalpha, it binds CD47, but with a lower affinity (K(d), approximately 23 microM) compared with SIRPalpha (K(d), approximately 2 microM). mAbs specific to SIRPgamma show that it was not expressed on myeloid cells, in contrast to SIRPalpha and -beta, being expressed instead on the majority of T cells and a proportion of B cells. The short cytoplasmic tail of SIRPgamma does not contain any known signaling motifs, nor does it contain a characteristic lysine, as with SIRPbeta, that is required for DAP12 interaction. DAP12 coexpression is a requirement for SIRPbeta surface expression, whereas SIRPgamma is expressed in its absence. The SIRPgamma-CD47 interaction may therefore not be capable of bidirectional signaling as with the SIRPalpha-CD47, but, instead, use unidirectional signaling via CD47 only.
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Gary
G
Brooke
Joanna D
JD
Holbrook
Marion H
MH
Brown
A Neil
AN
Barclay
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D051928:CD47 Antigen; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000502:physiology*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D039842:Neural Cell Adhesion Molecule L1 / Q000737:chemistry* / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000276:immunology / Q000502:physiology*; D020349:Surface Plasmon Resonance; D020298:U937 Cells
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D039842:Neural Cell Adhesion Molecule L1; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; C490691:SIRPG protein, human; C110546:TYROBP protein, human