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Gene Review

SH2D1A  -  SH2 domain containing 1A

Homo sapiens

Synonyms: DSHP, Duncan disease SH2-protein, EBVS, IMD5, LYP, ...
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Disease relevance of SH2D1A


High impact information on SH2D1A

  • Further analyses of the SAP/SH2D1A gene in XLP patients have made it clear that the development of dys-gammaglobulinemia and B cell lymphoma can occur without evidence of prior EBV infection [6].
  • It appears therefore that the SAP/SH2D1A gene controls signaling via the SLAM family of surface receptors and thus may play a fundamental role in T cell and APC interactions during viral infections [6].
  • Several lines of evidence, including structural studies and analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural inhibitor of SH2-domain-dependent interactions with members of the SLAM family [6].
  • Our understanding of the X-linked lymphoproliferative syndrome (XLP) has advanced significantly in the last two years [6].
  • Moreover, preliminary results of virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes [6].

Chemical compound and disease context of SH2D1A


Biological context of SH2D1A


Anatomical context of SH2D1A

  • SH2D1A is expressed in many tissues involved in the immune system [11].
  • NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease [8].
  • XLP is linked to mutations of the SAP/SH2D1A gene with dysregulated T-cell activation in response to EBV infection [12].
  • These data indicate that the cytotoxicity of activated NK cells is mediated by the association of 2B4 and SAP/SH2D1A, and that this association is dependent upon the activity of PI3K [13].
  • Here we report that SH2D1A is expressed in tonsillar B cells and in some B lymphoblastoid cell lines, where CD150 coprecipitates with SH2D1A and SHIP [14].

Associations of SH2D1A with chemical compounds

  • In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors [10].
  • Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase [13].
  • By bisulfite sequencing and methylation-sensitive restriction enzyme digestion, we show that a differential methylation pattern of CpG-rich regions in the 5' region and the adjacent exon 1 of the SH2D1A gene indeed correlates with the tissue-specific gene transcription [15].
  • We describe a patient with a novel serine-to-proline mutation at aa 57 in SAP and compare the location of the altered amino acid with all known missense mutations in the SAP-encoding SH2D1A gene, including those of 4 additional individuals whose cases have not been described elsewhere [16].
  • In addition, downstream serine/threonine kinases are constitutively active in CD4 T cells of XLP patients [17].

Physical interactions of SH2D1A


Enzymatic interactions of SH2D1A

  • In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation [21].

Regulatory relationships of SH2D1A


Other interactions of SH2D1A


Analytical, diagnostic and therapeutic context of SH2D1A


  1. The X-linked lymphoproliferative syndrome gene product SH2D1A associates with p62dok (Dok1) and activates NF-kappa B. Sylla, B.S., Murphy, K., Cahir-McFarland, E., Lane, W.S., Mosialos, G., Kieff, E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  2. The adaptor protein SH2D1A regulates signaling through CD150 (SLAM) in B cells. Mikhalap, S.V., Shlapatska, L.M., Yurchenko, O.V., Yurchenko, M.Y., Berdova, G.G., Nichols, K.E., Clark, E.A., Sidorenko, S.P. Blood (2004) [Pubmed]
  3. Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors. Li, C., Iosef, C., Jia, C.Y., Han, V.K., Li, S.S. J. Biol. Chem. (2003) [Pubmed]
  4. SH2D1A expression in Burkitt lymphoma cells is restricted to EBV positive group I lines and is downregulated in parallel with immunoblastic transformation. Nagy, N., Maeda, A., Bandobashi, K., Kis, L.L., Nishikawa, J., Trivedi, P., Faggioni, A., Klein, G., Klein, E. Int. J. Cancer (2002) [Pubmed]
  5. Expression of SH2D1A in five classical Hodgkin's disease-derived cell lines. Kis, L.L., Nagy, N., Klein, G., Klein, E. Int. J. Cancer (2003) [Pubmed]
  6. X-linked lymphoproliferative disease: a progressive immunodeficiency. Morra, M., Howie, D., Grande, M.S., Sayos, J., Wang, N., Wu, C., Engel, P., Terhorst, C. Annu. Rev. Immunol. (2001) [Pubmed]
  7. X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis. Kanegane, H., Ito, Y., Ohshima, K., Shichijo, T., Tomimasu, K., Nomura, K., Futatani, T., Sumazaki, R., Miyawaki, T. Am. J. Hematol. (2005) [Pubmed]
  8. NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. Bottino, C., Falco, M., Parolini, S., Marcenaro, E., Augugliaro, R., Sivori, S., Landi, E., Biassoni, R., Notarangelo, L.D., Moretta, L., Moretta, A. J. Exp. Med. (2001) [Pubmed]
  9. Molecular dissection of the signaling and costimulatory functions of CD150 (SLAM): CD150/SAP binding and CD150-mediated costimulation. Howie, D., Simarro, M., Sayos, J., Guirado, M., Sancho, J., Terhorst, C. Blood (2002) [Pubmed]
  10. Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients. Morra, M., Simarro-Grande, M., Martin, M., Chen, A.S., Lanyi, A., Silander, O., Calpe, S., Davis, J., Pawson, T., Eck, M.J., Sumegi, J., Engel, P., Li, S.C., Terhorst, C. J. Biol. Chem. (2001) [Pubmed]
  11. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Coffey, A.J., Brooksbank, R.A., Brandau, O., Oohashi, T., Howell, G.R., Bye, J.M., Cahn, A.P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., Leversha, M., Huckle, E., Shaw-Smith, C.J., Dunham, A., Rhodes, S., Schuster, V., Porta, G., Yin, L., Serafini, P., Sylla, B., Zollo, M., Franco, B., Bolino, A., Seri, M., Lanyi, A., Davis, J.R., Webster, D., Harris, A., Lenoir, G., de St Basile, G., Jones, A., Behloradsky, B.H., Achatz, H., Murken, J., Fassler, R., Sumegi, J., Romeo, G., Vaudin, M., Ross, M.T., Meindl, A., Bentley, D.R. Nat. Genet. (1998) [Pubmed]
  12. Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Chuang, H.C., Lay, J.D., Hsieh, W.C., Wang, H.C., Chang, Y., Chuang, S.E., Su, I.J. Blood (2005) [Pubmed]
  13. Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase. Aoukaty, A., Tan, R. J. Biol. Chem. (2002) [Pubmed]
  14. CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. Shlapatska, L.M., Mikhalap, S.V., Berdova, A.G., Zelensky, O.M., Yun, T.J., Nichols, K.E., Clark, E.A., Sidorenko, S.P. J. Immunol. (2001) [Pubmed]
  15. Differential methylation pattern of the X-linked lymphoproliferative (XLP) disease gene SH2D1A correlates with the cell lineage-specific transcription. Parolini, O., Weinhäusel, A., Kagerbauer, B., Sassmann, J., Holter, W., Gadner, H., Haas, O.A., Knapp, W. Immunogenetics (2003) [Pubmed]
  16. Fatal hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection in a patient with a novel mutation in the signaling lymphocytic activation molecule-associated protein. Halasa, N.B., Whitlock, J.A., McCurley, T.L., Smith, J.A., Zhu, Q., Ochs, H., Dermody, T.S., Crowe, J.E. Clin. Infect. Dis. (2003) [Pubmed]
  17. Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome. Nakamura, H., Zarycki, J., Sullivan, J.L., Jung, J.U. J. Immunol. (2001) [Pubmed]
  18. Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. Morra, M., Lu, J., Poy, F., Martin, M., Sayos, J., Calpe, S., Gullo, C., Howie, D., Rietdijk, S., Thompson, A., Coyle, A.J., Denny, C., Yaffe, M.B., Engel, P., Eck, M.J., Terhorst, C. EMBO J. (2001) [Pubmed]
  19. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Eissmann, P., Beauchamp, L., Wooters, J., Tilton, J.C., Long, E.O., Watzl, C. Blood (2005) [Pubmed]
  20. Expression of the SH2D1A gene is regulated by a combination of transcriptional and post-transcriptional mechanisms. Okamoto, S., Ji, H., Howie, D., Clarke, K., Gullo, C., Manning, S., Coyle, A.J., Terhorst, C. Eur. J. Immunol. (2004) [Pubmed]
  21. Role for glycogen synthase kinase-3 in NK cell cytotoxicity and X-linked lymphoproliferative disease. Aoukaty, A., Tan, R. J. Immunol. (2005) [Pubmed]
  22. Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP. Hare, N.J., Ma, C.S., Alvaro, F., Nichols, K.E., Tangye, S.G. Int. Immunol. (2006) [Pubmed]
  23. SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. Yin, L., Ferrand, V., Lavoué, M.F., Hayoz, D., Philippe, N., Souillet, G., Seri, M., Giacchino, R., Castagnola, E., Hodgson, S., Sylla, B.S., Romeo, G. Hum. Genet. (1999) [Pubmed]
  24. The role of CD150-SH2D1A association in CD150 signaling in Hodgkin's lymphoma cell lines. Yurchenko, M.Y., Kashuba, E.V., Shlapatska, L.M., Sivkovich, S.A., Sidorenko, S.P. Experimental oncology. (2005) [Pubmed]
  25. X-linked lymphoproliferative disease: genetics and biochemistry. Nichols, K.E. Reviews in immunogenetics. (2000) [Pubmed]
  26. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Nichols, K.E., Harkin, D.P., Levitz, S., Krainer, M., Kolquist, K.A., Genovese, C., Bernard, A., Ferguson, M., Zuo, L., Snyder, E., Buckler, A.J., Wise, C., Ashley, J., Lovett, M., Valentine, M.B., Look, A.T., Gerald, W., Housman, D.E., Haber, D.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  27. X-linked lymphoproliferative disease is caused by deficiency of a novel SH2 domain-containing signal transduction adaptor protein. Schuster, V., Kreth, H.W. Immunol. Rev. (2000) [Pubmed]
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