The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.
In addition to triggering the activation of B- or T-cell antigen receptors, the binding of a ligand to its receptor at the cell surface can sometimes determine the physiological outcome of interactions between antigen-presenting cells, T and B lymphocytes. The protein SLAM (also known as CDw150), which is present on the surface of B and T cells, forms such a receptor-ligand pair as it is a self-ligand. We now show that a T-cell-specific, SLAM-associated protein (SAP), which contains an SH2 domain and a short tall, acts as an inhibitor by blocking recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to a docking site in the SLAM cytoplasmic region. The gene encoding SAP maps to the same area of the X chromosome as the locus for X-linked lymphoproliferative disease (XLP) and we found mutations in the SAP gene in three XLP patients. Absence of the inhibitor SAP in XLP patients affects T/B-cell interactions induced by SLAM, leading to an inability to control B-cell proliferation caused by Epstein-Barr virus infections.
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. jortega@bidmc.harvard.edu
J
J
Sayos
C
C
Wu
M
M
Morra
N
N
Wang
X
X
Zhang
D
D
Allen
S
S
van Schaik
L
L
Notarangelo
R
R
Geha
M G
MG
Roncarolo
H
H
Oettgen
J E
JE
De Vries
G
G
Aversa
C
C
Terhorst
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004247:DNA; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution; D014960:X Chromosome; D018909:src Homology Domains
D015703:Antigens, CD; D002352:Carrier Proteins; D006023:Glycoproteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D004247:DNA; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn