T cell receptor-mediated signal transduction controlled by the beta chain transmembrane domain: apoptosis-deficient cells display unbalanced mitogen-activated protein kinases activities upon T cell receptor engagement.
The bases that support the versatility of the T cell receptor (TCR) to generate distinct T cell responses remain unclear. We have previously shown that mutant cells in the transmembrane domain of TCRbeta chain are impaired in TCR-induced apoptosis but are not affected in other functions. Here we describe the biochemical mechanisms by which this mutant receptor supports some T cell responses but fails to induce apoptosis. Extracellular signal-regulated protein kinase (ERK) is activated at higher and more sustained levels in TCRbeta-mutated than in wild type cells. Conversely, activation of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase is severely reduced in mutant cells. By attempting to link this unbalanced induction to altered upstream events, we found that ZAP-70 is normally activated. However, although SLP-76 phosphorylation is normally induced, TCR engagement of mutant cells results in lower tyrosine phosphorylation of LAT but in higher tyrosine phosphorylation of Vav than in wild type cells. The results suggest that an altered signaling cascade leading to an imbalance in mitogen-activated protein kinase activities is involved in the selective impairment of apoptosis in these mutant cells. Furthermore, they also provide new insights in the contribution of TCR to decipher the signals that mediate apoptosis distinctly from proliferation.
Teixeiro
Emma
E
Department of Immunology, Fundación Jiménez Diaz, Avenida. Reyes Católicos 2, 28040 Madrid, Spain.
Fuentes
Patricia
P
Galocha
Begona
B
Alarcon
Balbino
B
Bragado
Rafael
R
D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis; D006801:Humans; D019169:Jurkat Cells; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C497261:ZAP70 protein, human