Mitogen-activated kinase kinase kinase 1 regulates T cell receptor- and CD28-mediated signaling events which lead to NF-kappaB activation.
Optimal activation of Rel/NF-kappaB transcription factors in T lymphocytes requires a CD28-delivered co-stimulatory signal in addition to TCR engagement. Although, Rel/NF-kappaB transcription factors are critical regulators of many T cell functions, the mechanisms and molecules, which link the surface receptors to their activation, are poorly characterized. Using Jurkat T cells stimulated with superantigen presented on B7-positive APC, we showed that CD28- and TCR-stimulated NF-kappaB-dependent transcription is associated to the activation of IkappaB kinase beta (IKKbeta) and, to a lesser extent, of IkappaB kinase alpha (IKKalpha). A dominant negative mutant of the MAP3 kinase MEKK1, a kinase known to regulate the JNK pathway and to activate NF-kappaB-dependent transcription in many cell types, strongly inhibits CD28- and TCR-induced IKK activity, whereas the dominant negative mutants of the NF-kappaB-inducing kinase (NIK) did not exert any significant effects. In addition, TCR/CD28 stimulation results in the recruitment and autophosphorylation of endogenous MEKK1, whereas endogenous NIK was not detectably activated. Our data identify MEKK1 as a critical step in coupling signals initiated by TCR and CD28 to the downstream pathways which lead to both AP-1 and NF-kappaB activation in T lymphocytes.
Tuosto
L
L
Department of Cellular and Developmental Biology, University of Rome La Sapienza, Italy. tuosto@axcasp.caspur.it
Costanzo
A
A
Guido
F
F
Marinari
B
B
Vossio
S
S
Moretti
F
F
Levrero
M
M
Piccolella
E
E
D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D019169:Jurkat Cells; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*
D018122:B7-1 Antigen; D018106:CD28 Antigens; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases