Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2.
T cells play a central role in the recognition and elimination of foreign pathogens. Signals through the T cell receptor (TCR) control the extent and duration of the T cell response. To ensure that T cells are not inappropriately activated, signaling pathways downstream of the TCR are subject to multiple levels of positive and negative regulation. Herein, we describe two related proteins, Sts-1 and Sts-2, that negatively regulate TCR signaling. T cells from mice lacking Sts-1 and Sts-2 are hyperresponsive to TCR stimulation. The phenotype is accompanied by increased Zap-70 phosphorylation and activation, including its ubiquitinylated forms. Additionally, hyperactivation of signaling proteins downstream of the TCR, a marked increase in cytokine production by Sts1/2(-/-) T cells, and increased susceptibility to autoimmunity in a mouse model of multiple sclerosis is observed. Therefore, Sts-1 and Sts-2 are critical regulators of the signaling pathways that regulate T cell activation.
Carpino
Nick
N
Department of Biochemistry, Saint Jude Children's Research Hospital, Memphis, TN 38105, USA.
Turner
Steve
S
Mekala
Divya
D
Takahashi
Yutaka
Y
Zang
Heesuk
H
Geiger
Terrence L
TL
Doherty
Peter
P
Ihle
James N
JN
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D051746:ZAP-70 Protein-Tyrosine Kinase
D011948:Receptors, Antigen, T-Cell; C482177:Sts-2 protein, mouse; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse