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Anne Marie-Cardine^*, Henning Kirchgessner^*, Eddy Bruyns^*, Andrej Shevchenko, Matthias Mann, Frank Autschbach, Sheldon Ratnofsky^||, Stefan Meuer^*, and Burkhart Schraven^*

From the ^* Immunomodulation Laboratory of the Institute for Immunology, and the Institute for Pathology, University of Heidelberg, 69120 Heidelberg, Germany; the Protein and Peptide Group, European Molecular Biology Laboratories, 69117 Heidelberg, Germany; and the ^|| BASF Bioresearch Corporation, Worcester, Massachusetts 01605

T lymphocytes express several low molecular weight transmembrane adaptor proteins that recruit src homology (SH)2 domain–containing intracellular molecules to the cell membrane via tyrosine-based signaling motifs. We describe here a novel molecule of this group termed SIT (SHP2 interacting transmembrane adaptor protein). SIT is a disulfide-linked homodimeric glycoprotein that is expressed in lymphocytes. After tyrosine phosphorylation by src and possibly syk protein tyrosine kinases SIT recruits the SH2 domain–containing 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 activated T cells (NF-AT) by interfering with signaling processes that are probably located upstream of activation of phospholipase C. However, binding of SHP2 to SIT is not required for inhibition of NF-AT induction, suggesting that SIT not only regulates NF-AT activity but also controls NF-AT unrelated pathways of T cell activation involving SHP2.

Key Words: T lymphocytes • T cell receptor • transmembrane adaptor proteins • signal transduction

Anne Marie-Cardine is a recipient of a fellowship from the Training and Mobility of Researchers program of the European Community (ERBFMBICT950472). This work was supported in part by Deutsche Forschungsgemeinschaft grants SCHR/533/1-1 and SCHR/533/4-1 and by Sonderforschungsbereich (SFB) 405, projects A5 (to B. Schraven) and B9 (to F. Autschbach). The work in M. Mann's laboratory was partially supported by a grant from the German Technology Ministry (BMBF).

M. Mann's present address is Center of Experimental Bioinformatics, Odense University, Campusveij 55, DK-5230 Odense M, Denmark.

Anne Marie-Cardine and Henning Kirchgessner contributed equally to this work.

Abbreviations used: aa, amino acid; EST, expressed sequence tag; Grb2, growth factor receptor binding protein 2; IEF, isoelectric focusing; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine based inhibition motif; LAT, linker for activation of T cells; NF-AT, nuclear factor of activated T cells; PI3-K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTK, protein tyrosine kinase; PTYR, phosphotyrosine; SH, src homology; SHIP, SH2 containing inositol phosphatase; SHP, SH2 containing protein tyrosine phosphatase; SIT, SHP2-interacting transmembrane adaptor protein; SLP, SH2 domain containing leukocyte phosphoprotein; TRIM, T cell receptor–interacting molecule.

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