Alternative titles; symbolsT-CELL SH2 DOMAIN-CONTAINING ADAPTOR PROTEIN; TSADHGNC Approved Gene Symbol: SH2D2ACytogenetic location: 1q23.1 Genomic coordinate...
Alternative titles; symbols
HGNC Approved Gene Symbol: SH2D2A
Cytogenetic location: 1q23.1 Genomic coordinates (GRCh38): 1:156,806,237-156,816,852 (from NCBI)
▼ Cloning and Expression
Adaptor proteins link catalytic signaling proteins to cell surface receptors or downstream effector proteins. Using a subtractive hybridization strategy to identify genes specifically expressed in activated CD8 (see 186910)-positive T cells, Spurkland et al. (1998) isolated cDNAs encoding SH2D2A, which they named TSAD. The predicted 389-amino acid SH2D2A protein contains an Src homology-2 (SH2) domain, putative SH3 domain-binding motifs, and putative phosphotyrosine-binding domain (PTB)-binding motifs, but no catalytic domains. The authors also isolated cDNAs representing alternatively spliced SH2D2A transcripts that encode deduced 361- and 399-amino acid proteins. Northern blot analysis detected an approximately 1.7-kb SH2D2A transcript in peripheral blood leukocytes, thymus, and spleen. SH2D2A was expressed in activated T cells, but not in resting T cells or in B cells. Its expression was rapidly induced after activation of T cells. Antiserum raised against SH2D2A reacted with a 52-kD protein on Western blots of T-cell lysates. Recombinant SH2D2A expressed in mammalian cells localized to the cytoplasm. Spurkland et al. (1998) showed that SH2D2A is tyrosine-phosphorylated in vivo. They suggested that SH2D2A is an adaptor protein involved in T cell signaling.
▼ Gene Function
Using T cells from Tsad-deficient mice, Marti et al. (2006) showed that the major role of Tsad in cytoplasm is activation of Lck (153390) protein tyrosine kinase. Consequently, Tsad regulates several downstream signaling events. Yeast multihybrid analysis showed that Tsad regulates Lck directly through physical interaction with the Lck SH3 and SH2 domains. Marti et al. (2006) concluded that TSAD is a positive regulator of proximal T-cell receptor signal transduction.
Spurkland et al. (1998) mapped the SH2D2A gene to chromosome 1 using a somatic cell hybrid panel. By FISH, they localized the SH2D2A gene to chromosome 1q21.
▼ Animal Model
Drappa et al. (2003) found that Tsad deficiency on a mouse background strain not prone to autoimmunity resulted in hypergammaglobulinemia in all Ig subclasses, with development of antinuclear antibodies and, in older mice, antibodies against single- and double-stranded DNA. Older Tsad -/- mice showed kidney disease, including signs of glomerulonephritis, and perivascular accumulation of leukocytes in lung, suggestive of a lupus-like syndrome. Younger Tsad -/- mice showed increased susceptibility to experimentally induced lupus-like disease. In addition, older Tsad -/- mice accumulated large numbers of activated T and B cells in spleen and displayed defective T-cell death in vivo. Drappa et al. (2003) concluded that TSAD is a critical regulator of T-cell death whose absence promotes lupus-like autoimmunity.