SLP-76 Is a Direct Substrate of SHP-1 Recruited to Killer Cell Inhibitory Receptors

• Published in: The Journal of biological chemistry 1998-10, Vol.273 (42), p.27518-27523
• Main Authors: Binstadt, Bryce A., Billadeau, Daniel D., Jevremović, Dragan, Williams, Brandi L., Fang, Nan, Yi, Taolin, Koretzky, Gary A., Abraham, Robert T., Leibson, Paul J.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Catalytic Domain; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Humans; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural - immunology; Phosphopeptides - metabolism; Phosphoproteins - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - metabolism; Receptors, Immunologic - metabolism; Receptors, KIR; SH2 Domain-Containing Protein Tyrosine Phosphatases; Signal Transduction; Substrate Specificity; T-Lymphocytes, Cytotoxic - immunology; Vaccinia virus - immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.42.27518

Activation of immune system cells via antigen-, Fc-, or natural killer cell-triggering-receptor stimulation is aborted by co-engagement of inhibitory receptors. Negative signaling by killer cell inhibitory receptors and related receptors depends on the Src homology 2 (SH2)-containing protein tyrosine phosphatase SHP-1. Using a combination of direct binding and functional assays, we demonstrated that the SH2 domain-containing leukocyte protein 76 (SLP-76) is a specific target for dephosphorylation by SHP-1 in T cells and natural killer cells. Furthermore, we showed that tyrosine-phosphorylated SLP-76 is required for optimal activation of cytotoxic lymphocytes, suggesting that the targeted dephosphorylation of SLP-76 by SHP-1 is an important mechanism for the negative regulation of immune cell activation by inhibitory receptors.