Disease relevance of SH2D1A

• Thus, SH2D1A can affect multiple intracellular signaling pathways that are potentially important in the normal effective host response to Epstein-Barr virus infection [1].
• Analysis of CD150 and SH2D1A expression in non-Hodgkin and Hodgkin lymphomas revealed stages of B-cell differentiation where these molecules are expressed alone or coexpressed [2].
• 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 [3].
• SH2D1A expression in Burkitt lymphoma cells is restricted to EBV positive group I lines and is downregulated in parallel with immunoblastic transformation [4].
• We now show SH2D1A in 5 EBV-negative classical Hodgkin's disease (HD)-derived cell lines [5].

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

• In this study, we describe a Japanese XLP patient who presented with hypogammaglobulinemia following acute EBV-induced infectious mononucleosis in the infancy and later had systemic lymphocytic vasculitis and hemophagocytic lymphohistiocytosis in the adulthood, which resolved by steroid pulse therapy [7].

Biological context of SH2D1A

• NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain-containing protein (SH2D1A) as well as with SH2 domain-containing phosphatases (SHPs) [8].
• NF-kappaB activation by SH2D1A does not depend on the wild-type SH2 domain and is inhibited by a dominant-negative IkappaB kinase beta [1].
• CD150-induced signal transduction is controlled by SAP/SH2D1A, the gene that is aberrant in X-linked lymphoproliferative disease and familial hemophagocytic lymphohistiocytosis [9].
• Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients [10].
• One B-HD line, which originated from nodular lymphocyte-predominant Hodgkin's lymphoma and differed in phenotype, was SH2D1A-negative [5].

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

• The T and natural killer (NK) cell-specific gene SAP (SH2D1A) encodes a 'free SH2 domain' that binds a specific tyrosine motif in the cytoplasmic tail of SLAM (CD150) and related cell surface proteins [18].
• Signaling lymphocyte activation molecule-associated protein (SAP) can bind to all 4 ITSMs of 2B4 in a phosphorylation-dependent manner [19].
• As judged by RNA-gel mobility shift assays, this rapid degradation of SH2D1A mRNA was due to a balance in binding of the factors AUF1 and HuR to its 3' UTR [20].

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

• SH2D1A protein levels are up-regulated by CD40 cross-linking and down-regulated by B cell receptor ligation [14].
• The adaptor protein SH2D1A regulates signaling through CD150 (SLAM) in B cells [2].

Other interactions of SH2D1A

• We now report that SH2D1A associates with Dok1, a protein that interacts with Ras-GAP, Csk, and Nck [1].
• SAP acts as an inhibitor of interactions between 2B4 and these negative regulatory molecules, explaining how 2B4 inhibits NK-cell activation in the absence of functional SAP, as occurs in cells from patients with X-linked lymphoproliferative syndrome (XLP) [19].
• CD150-mediated Akt phosphorylation required Syk and SH2D1A, was negatively regulated by Lyn and Btk, but was SHIP independent [2].
• However, in SH2D1A-negative B cell lines, including B cell lines from X-linked lymphoproliferative syndrome patients, CD150 associates only with SHP-2 [14].
• X-linked lymphoproliferative disease (XLP) is an immunodeficiency resulting from mutations in SH2D1A, which encodes signalling lymphocytic activation molecule (SLAM)-associated protein (SAP) [22].

Analytical, diagnostic and therapeutic context of SH2D1A

• We have carried out a systematic mutation study of the SH2D1A gene in our series of 19 typical and 8 atypical XLP patients by polymerase chain reaction (PCR), reverse transcription/PCR, and sequencing, and have reconstructed the haplotypes of the patients [23].
• METHODS: The expression of CD150 splicing forms and SH2D1A adaptor protein in HD primary lymphoma tissue and cell lines were analyzed by RT-PCR method [24].
• Unlike other SH2 domain-containing proteins, DSHP associates with both phosphorylated and non-phosphorylated tyrosine residues, and crystallography studies have revealed novel properties of the DSHP SH2 domain [25].
• Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms [26].
• Successful transplanta tion of hematopoietic stem cells can cure this immunodeficiency In the future, gene therapy may eventually become an additional option to prevent XLP [27].

References