Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP.
X-linked lymphoproliferative disease (XLP) is a rare immune disorder commonly triggered by infection with Epstein-Barr virus. Major disease manifestations include fatal acute infectious mononucleosis, B-cell lymphoma, and progressive dys-gammaglobulinemia. SAP/SH2D1A, the product of the gene mutated in XLP, is a small protein that comprises a single SH2 domain and a short tail of 26 amino acids. SAP binds to a specific motif in the cytoplasmic tails of the cell surface receptors SLAM and 2B4, where it blocks recruitment of the phosphatase SHP-2. Here it is reported that Ly-9 and CD84, 2 related glycoproteins differentially expressed on hematopoietic cells, also recruit SAP. Interactions between SAP and Ly-9 or CD84 were analyzed using a novel yeast 2-hybrid system, by COS cell transfections and in lymphoid cells. Recruitment of SAP is most efficient when the specific tyrosine residues in the cytoplasmic tails of Ly-9 or CD84 are phosphorylated. It is concluded that in activated T cells, the SAP protein binds to and regulates signal transduction events initiated through the engagement of SLAM, 2B4, CD84, and Ly-9. This suggests that combinations of dysfunctional signaling pathways initiated by these 4 cell surface receptors may cause the complex phenotypes of XLP. (Blood. 2001;97:3867-3874)
Sayós
J
J
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline Ave., Boston, MA 02215, USA.
Martín
M
M
Chen
A
A
Simarro
M
M
Howie
D
D
Morra
M
M
Engel
P
P
Terhorst
C
C
D015703:Antigens, CD / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D008040:Genetic Linkage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins; D010766:Phosphorylation; D011485:Protein Binding; D011940:Receptor Aggregation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014960:X Chromosome
D015703:Antigens, CD; C498970:CD84 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C430423:LY9 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family