Sts-2 Is a Phosphatase That Negatively Regulates Zeta-associated Protein (ZAP)-70 and T Cell Receptor Signaling Pathways

• Published in: The Journal of biological chemistry Vol. 286; no. 18; pp. 15943 - 15954
• Main Authors: San Luis, Boris, Sondgeroth, Ben, Nassar, Nicolas, Carpino, Nick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.05.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Enzyme Activation - physiology; Immunology; Lymphocyte Activation - physiology; Mice; Mice, Knockout; Phosphatase; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - immunology; Phosphoprotein Phosphatases - metabolism; Phosphorylation - physiology; Phosphotyrosine Signaling; Protein Tyrosine Phosphatases; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Signal Transduction; Signal Transduction - physiology; Substrate Specificity - physiology; T Cell Receptor; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; ZAP-70 Protein-Tyrosine Kinase - genetics; ZAP-70 Protein-Tyrosine Kinase - immunology; ZAP-70 Protein-Tyrosine Kinase - metabolism; T Cell Receptor; Phosphotyrosine Signaling; Immunology; Signal Transduction; Phosphatase
• DOI: 10.1074/jbc.M110.177634
• ISSN: 0021-9258

T cell activity is controlled in large part by the T cell receptor (TCR). The TCR detects the presence of foreign pathogens and activates the T cell-mediated immune reaction. Numerous intracellular signaling pathways downstream of the TCR are involved in the process of T cell activation. Negative regulation of these pathways helps prevent excessive and deleterious T cell responses. Two homologous proteins, Sts-1 and Sts-2, have been shown to function as critical negative regulators of TCR signaling. The phosphoglycerate mutase-like domain of Sts-1 (Sts-1PGM) has a potent phosphatase activity that contributes to the suppression of TCR signaling. The function of Sts-2PGM as a phosphatase has been less clear, principally because its intrinsic enzyme activity has been difficult to detect. Here, we demonstrate that Sts-2 regulates the level of tyrosine phosphorylation on targets within T cells, among them the critical T cell tyrosine kinase Zap-70. Utilizing new phosphorylated substrates, we demonstrate that Sts-2PGM has clear, albeit weak, phosphatase activity. We further pinpoint Sts-2 residues Glu-481, Ser-552, and Ser-582 as specificity determinants, in that an Sts-2PGM triple mutant in which these three amino acids are altered to their counterparts in Sts-1PGM has substantially increased activity. Our results suggest that the phosphatase activities of both suppressor of TCR signaling homologues cooperate in a similar but independent fashion to help set the threshold for TCR-induced T cell activation.