Protein kinase C and calcineurin synergize to activate IkappaB kinase and NF-kappaB in T lymphocytes.
The nuclear factor of kappaB (NF-kappaB) is a ubiquitous transcription factor that is key in the regulation of the immune response and inflammation. T cell receptor (TCR) cross-linking is in part required for activation of NF-kappaB, which is dependent on the phosphorylation and degradation of IkappaBalpha. By using Jurkat and primary human T lymphocytes, we demonstrate that the simultaneous activation of two second messengers of the TCR-initiated signal transduction, protein kinase C (PKC) and calcineurin, results in the synergistic activation of the IkappaBalpha kinase (IKK) complex but not of another putative IkappaBalpha kinase, p90(rsk). We also demonstrate that the IKK complex, but not p90(rsk), is responsible for the in vivo phosphorylation of IkappaBalpha mediated by the co-activation of PKC and calcineurin. Each second messenger is necessary, as inhibition of either one reverses the activation of the IKK complex and IkappaBalpha phosphorylation in vivo. Overexpression of dominant negative forms of IKKalpha and -beta demonstrates that only IKKbeta is the target for PKC and calcineurin. These results indicate that within the TCR/CD3 signal transduction pathway both PKC and calcineurin are required for the effective activation of the IKK complex and NF-kappaB in T lymphocytes.
Trushin
S A
SA
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Pennington
K N
KN
Algeciras-Schimnich
A
A
Paya
C V
CV
D001483:Base Sequence; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*
D017931:DNA Primers; D016328:NF-kappa B; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D011493:Protein Kinase C; D019703:Calcineurin; D002118:Calcium