{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:19:29Z","timestamp":1779344369112,"version":"3.51.4"},"reference-count":25,"publisher":"American Society of Hematology","issue":"12","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,6,15]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1182\/blood.v97.12.3867","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:47Z","timestamp":1027774007000},"page":"3867-3874","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":98,"title":["Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP"],"prefix":"10.1182","volume":"97","author":[{"given":"Joan","family":"Sayo\u0301s","sequence":"first","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"Mart\u0131\u0301n","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u0131\u0301a","family":"Simarro","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duncan","family":"Howie","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Morra","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Engel","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cox","family":"Terhorst","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; the Immunology Unit, Department of Cellular Biology and Pathology, IDIBAPS, Medical School, University of Barcelona, Spain."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2020021221424587100_B1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/S0140-6736(75)92004-8","article-title":"X-linked recessive progressive combined variable immunodeficiency.","volume":"1","author":"Purtilo","year":"1975","journal-title":"Lancet."},{"key":"2020021221424587100_B2","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/26683","article-title":"The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.","volume":"395","author":"Sayos","year":"1998","journal-title":"Nature."},{"key":"2020021221424587100_B3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/2424","article-title":"Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.","volume":"20","author":"Coffey","year":"1998","journal-title":"Nat Genet."},{"key":"2020021221424587100_B4","doi-asserted-by":"crossref","first-page":"13765","DOI":"10.1073\/pnas.95.23.13765","article-title":"Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.","volume":"95","author":"Nichols","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021221424587100_B5","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.4049\/jimmunol.162.12.6981","article-title":"Human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.","volume":"162","author":"Tangye","year":"1999","journal-title":"J Immunol."},{"key":"2020021221424587100_B6","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.4049\/jimmunol.165.6.2932","article-title":"Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome.","volume":"165","author":"Tangye","year":"2000","journal-title":"J Immunol."},{"key":"2020021221424587100_B7","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1084\/jem.192.3.337","article-title":"X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells.","volume":"192","author":"Parolini","year":"2000","journal-title":"J Exp Med."},{"key":"2020021221424587100_B8","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1093\/intimm\/12.12.1749","article-title":"Potential pathways for regulation of NK and T cell responses: differential X-linked lymphoproliferative syndrome gene product SAP interactions with SLAM and 2B4.","volume":"12","author":"Sayos","year":"2000","journal-title":"Int Immunol."},{"key":"2020021221424587100_B9","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.4049\/jimmunol.165.7.3549","article-title":"Defective natural killer cell activation in X-linked lymphoproliferative disease.","volume":"7","author":"Benoit","year":"2000","journal-title":"J Immunol."},{"key":"2020021221424587100_B10","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S1097-2765(00)80206-3","article-title":"Crystal structures of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition.","volume":"4","author":"Poy","year":"1999","journal-title":"Mol Cell."},{"key":"2020021221424587100_B11","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/376260a0","article-title":"A novel receptor involved in T-cell activation.","volume":"376","author":"Cocks","year":"1995","journal-title":"Nature."},{"key":"2020021221424587100_B12","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.4049\/jimmunol.158.9.4036","article-title":"Engagement of the signaling lymphocytic activation molecule (SLAM) on activated T cells results in IL-2-independent, cyclosporin A-sensitive T cell proliferation and IFN-gamma production.","volume":"158","author":"Aversa","year":"1997","journal-title":"J Immunol."},{"key":"2020021221424587100_B13","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/icb.1997.30","article-title":"SLAM and its role in T cell activation and Th responses.","volume":"75","author":"Aversa","year":"1997","journal-title":"Immunol Cell Biol."},{"key":"2020021221424587100_B14","doi-asserted-by":"crossref","first-page":"4316","DOI":"10.4049\/jimmunol.159.9.4316","article-title":"Reversal of human allergic T helper 2 responses by engagement of signaling lymphocytic activation molecule.","volume":"159","author":"Carballido","year":"1997","journal-title":"J Immunol."},{"key":"2020021221424587100_B15","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1084\/jem.185.6.993","article-title":"Soluble and membrane-bound forms of signaling lymphocytic activation molecule (SLAM) induce proliferation and Ig synthesis by activated human B lymphocytes.","volume":"185","author":"Punnonen","year":"1997","journal-title":"J Exp Med."},{"key":"2020021221424587100_B16"},{"key":"2020021221424587100_B17","doi-asserted-by":"crossref","first-page":"5328","DOI":"10.4049\/jimmunol.151.10.5328","article-title":"Cloning and characterization of the 2B4 gene encoding a molecule associated with non-MHCrestricted killing mediated by activated natural killer cells and T cells.","volume":"151","author":"Mathew","year":"1993","journal-title":"J Immunol."},{"key":"2020021221424587100_B18","doi-asserted-by":"crossref","first-page":"60","DOI":"10.4049\/jimmunol.151.1.60","article-title":"A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells.","volume":"151","author":"Garni-Wagner","year":"1993","journal-title":"J Immunol."},{"key":"2020021221424587100_B19","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1084\/jem.188.11.2083","article-title":"2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48.","volume":"188","author":"Brown","year":"1998","journal-title":"J Exp Med."},{"key":"2020021221424587100_B20","doi-asserted-by":"crossref","first-page":"7563","DOI":"10.4049\/jimmunol.162.12.7563","article-title":"C1.7 antigen expression on CD8+ T cells in HIV-1-infected patients with progressing disease.","volume":"162","author":"Peritt","year":"1997","journal-title":"J Immunol."},{"key":"2020021221424587100_B21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0198-8859(99)00170-6","article-title":"2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism.","volume":"61","author":"Nakajima","year":"2000","journal-title":"Hum Immunol."},{"key":"2020021221424587100_B22","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1084\/jem.169.3.1087","article-title":"Blast-1 possesses a glycosyl-phosphatidylinositol (GPI) membrane anchor, is related to LFA3 and OX-45, maps to chromosome 1q21\u201323.","volume":"169","author":"Staunton","year":"2000","journal-title":"J Exp Med."},{"key":"2020021221424587100_B23","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1182\/blood.V90.6.2398","article-title":"CD84 leukocyte antigen is a new member of the Ig superfamily.","volume":"90","author":"de la Fuente","year":"1997","journal-title":"Blood."},{"key":"2020021221424587100_B24","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/S0952-7915(00)00123-0","article-title":"The gene defective in X-linked lymphoproliferative disease controls T cell dependent immune surveillance against Epstein-Barr virus.","volume":"12","author":"Howie","year":"2000","journal-title":"Curr Opin Immunol."},{"key":"2020021221424587100_B25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1006\/smim.2000.0217","article-title":"The CD2subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells.","volume":"12","author":"Tangye","year":"2000","journal-title":"Semin Immunol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/97\/12\/3867\/1674860\/h8120103867.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/97\/12\/3867\/1674860\/h8120103867.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,23]],"date-time":"2023-04-23T20:11:05Z","timestamp":1682280665000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/97\/12\/3867\/107203\/Cell-surface-receptors-Ly9-and-CD84-recruit-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,6,15]]},"references-count":25,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2001,6,15]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.v97.12.3867","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2001,6,15]]}}}