SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activation

T lymphocytes express several low molecular weight transmembrane adaptor pr oteins that recruit src homology (SH)2 domain-containing intracellular mole cules to the cell membrane via tyrosine-based signaling motifs. We describe here a novel molecule of this group termed SIT (SHP2 interacting transmemb rane adaptor protein). SIT is a disulfide-linked homodimeric glycoprotein t hat is expressed in lymphocytes. After tyrosine phosphorylation by src and possibly syk protein tyrosine kinases SIT recruits the SH2 domain-containin g tyrosine phosphatase SHP2 via an immunoreceptor tyrosine-based inhibition motif. Overexpression of SIT in Jurkat cells downmodulates T cell receptor - and phytohemagglutinin-mediated activation of the nuclear factor of activ ated T cells (NF-AT) by interfering with signaling processes that are proba bly located upstream of activation of phospholipase C. However, binding of SHP2 to SIT is not required for inhibition of NF-AT induction, suggesting t hat SIT not only regulates NF-AT activity but also controls NF-AT unrelated pathways of T cell activation involving SHP2.