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SHP2-INTERACTING TRANSMEMBRANE ADAPTOR PROTEIN 1; SIT1

SHP2-INTERACTING TRANSMEMBRANE ADAPTOR PROTEIN 1; SIT1

HGNC Approved Gene Symbol: SIT1Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,649,294-35,650,930 (from NCBI)▼ TEXTT-cell activation requires...

HGNC Approved Gene Symbol: SIT1

Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,649,294-35,650,930 (from NCBI)

▼ TEXT
T-cell activation requires stimulation of the T-cell receptor (TCR; see 186880)-CD3 (see CD3Z; 186780) complex, followed by recruitment of an array of intracellular signaling proteins (e.g., GRB2 (108355) and PLCG1 (172420)). Mediating the interaction between the extracellular receptors and intracellular signaling pathways are adaptor proteins such as LAT (602354) and TRIM (604962).

▼ Cloning and Expression
By tryptic peptide sequence analysis of a 30/40-kD disulfide-linked homodimeric glycoprotein that had been copurified with TRIM, followed by searching an EST database, Marie-Cardine et al. (1999) identified a cDNA encoding a deduced 196-amino acid protein that they designated SIT. Sequence analysis predicted that SIT has a putative 22-amino acid hydrophobic leader peptide, an 18-amino acid extracellular domain containing a potential N-glycosylation site and a cys residue that may be involved in an interchain disulfide bond, a 20-amino acid transmembrane domain, and a 136-amino acid intracellular portion containing several potential phosphorylation sites. SIT also contains 6 tyrosine residues, 5 of which may be involved in Src (190090) homology-2 (SH2) domain-mediated protein-protein interactions after phosphorylation. The cytoplasmic portion of SIT possesses a potential immunoreceptor tyrosine-based inhibitory motif, or ITIM, suggesting the potential for interactions with SHP1 (PTPN6; 176883) or SHP2 (PTPN11; 176876). Western blot analysis demonstrated that SIT is expressed as an approximately 40-kD protein that is reduced to approximately 20 kD by endoglycosidase treatment. Northern blot analysis detected strong expression of an approximately 1.6-kb SIT transcript in thymus, with lower expression detected in spleen and lymph nodes. Weak expression was detected in peripheral blood leukocytes, bone marrow, and T cell lines, but no expression was detected in monocytic cell lines. Immunofluorescence microscopy and immunoprecipitation analysis localized overexpressed SIT in cell membranes. Western blot analysis showed that SIT is a substrate for the Src protein kinases FYN (137025) and LCK (153390), as well as for ZAP70 (176947). Overexpressed SIT was shown to act as a negative regulator for transcriptional activity of the nuclear factor of activated T cells (NFAT; see 600489) via a mechanism upstream of phospholipase C (see PLCG1; 172420), and SIT recruits SHP2 but not SHP1 to the cell membrane via the ITIM.

▼ Gene Structure
Hubener et al. (2001) determined that the SIT gene contains 5 exons and spans 1.8 kb of genomic DNA. The SIT promoter demonstrated strong transcriptional activity and potential binding sites for both ubiquitous and lymphoid-specific transcription factors.

▼ Mapping
By FISH, Hubener et al. (2001) mapped the SIT1 gene to chromosome 9p13-p12.

Tags: 9p13.3