Disease relevance of SH2D2A

• Our recent studies indicate that homozygosity for short (ie GA(13) and GA(16)) alleles of the SH2D2A gene promoter is associated with development of multiple sclerosis [1].
• To study whether the same SH2D2A promoter polymorphism also contributes to the genetic susceptibility to develop juvenile rheumatoid arthritis (JRA), we examined 210 JRA patients and 558 healthy unrelated controls from Norway [1].
• These observations identify VRAP as an adaptor that recruits cytoplasmic signaling proteins to KDR, which plays an important role in normal and pathological angiogenesis [2].
• Studies in mouse and man have indicated that reduced expression of TSAd in T cells may predispose toward the development of autoimmune disease [3] .

High impact information on SH2D2A

• Here, we demonstrate that a substantial fraction of TSAd is found in the T cell nucleus [4].
• Further, we show that this augmentation requires a functional TSAd SH2 domain [4].
• Furthermore, the TSAd SH2 domain appears to be essential for this transcription-activating function independent of its role in nuclear import [4].
• Consistent with a role as a transcription activator, cotransfection of TSAd with an IL-2 promoter-reporter gene construct results in a considerable upregulation of IL-2 promoter activity [4] ,[5].

Biological context of SH2D2A

• Our data indicate that the 'short' alleles of the SH2D2A promoter could contribute to the genetic susceptibility to JRA [1].
• Physical mapping of a PAC and BAC contig containing the CD1 gene cluster telomeric to D1S2624 failed to identify a clone harboring the SH2D2A gene [6].
• Thus, transcriptional regulation of the SH2D2A gene in activated T cells is critically dependent on a CRE in the proximal promoter region [7].
• The minimal SH2D2A promoter was located between position -236 and -93 bp from the first coding ATG, and transcriptional activity in primary T cells depended on a cAMP response element (CRE) centered around position -117 [7].
• Reporter gene assays demonstrated that the proximal 1-kb SH2D2A promoter was constitutively active in Jurkat TAg T cells and, to a lesser extent, in K562 myeloid cells, Reh B cells, and 293T fibroblast cells [7].

Anatomical context of SH2D2A

• T-cell-specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the negative control of T-cell activation [1].
• cDNA cloning of a rat orthologue of SH2D2A encoding T-cell-specific adaptor protein (TSAd): expression in T and NK cells [8].
• VRAP is an adaptor protein encoded by the SH2D2A gene that binds KDR, a receptor for vascular endothelial cell growth factor (i.e. VEGFR-2) [2].
• The protein expressed by F2771 cDNA in transfected COS cells is localized in the cytoplasm [9].
• Northern blot analysis identified multiple VRAP transcripts in peripheral leukocytes, spleen, thymus, heart, lung, and human umbilical vein endothelial cells (HUVEC) [2].

Associations of SH2D2A with chemical compounds

• Transcriptional activation of the SH2D2A gene is dependent on a cyclic adenosine 5'-monophosphate-responsive element in the proximal SH2D2A promoter [7].
• Structure function analysis of SH2D2A isoforms expressed in T cells reveals a crucial role for the proline rich region encoded by SH2D2A exon 7 [10].
• Two-hybrid mapping showed that the VEGF receptor-associated protein (VRAP) interacted with tyrosine 951 in the kinase insert domain of KDR [2].
• Molecular cloning of a T cell-specific adapter protein (TSAd) containing an Src homology (SH) 2 domain and putative SH3 and phosphotyrosine binding sites [9] .

Regulatory relationships of SH2D2A

• In HUVEC, VEGF promotes association of VRAP with KDR [2].

Other interactions of SH2D2A

• Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene [1].
• No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed [11].
• The predominant VRAP mRNA encodes a 389-amino acid protein that contains an SH2 domain and a C-terminal proline-rich motif [2].
• HSH2: a novel SH2 domain-containing adapter protein involved in tyrosine kinase signaling in hematopoietic cells [12].

Analytical, diagnostic and therapeutic context of SH2D2A

• Consistent with this observation, we found that a cAMP analog was a very potent inducer of SH2D2A mRNA expression in primary T cells as measured by real-time RT-PCR [7].
• Unlike control and SCAP transfected cells, CCTalpha in SRD 4 cells was localized by immunofluorescence to the nuclear envelope, suggesting that residual enzyme activity in these cells was in an active membrane-associated form [13].
• We have isolated its rat homologue ( rSH2D2A) from an NK cell cDNA library and mapped the corresponding gene to chromosome 2 with a hamster-rat radiation hybrid cell panel. rSH2D2A encodes a 376 amino acid protein (rTSAd) which shows greater homology to mouse than human TSAd [8].

References