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Molecular and Cellular Biology, October 2003, p. 7068-7081, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.7068-7081.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Protein Kinase C{alpha} (PKC{alpha}) Acts Upstream of PKC{theta} To Activate I{kappa}B Kinase and NF-{kappa}B in T Lymphocytes

Sergey A. Trushin,1 Kevin N. Pennington,1 Eva M. Carmona,1 Susana Asin,1 Doris N. Savoy,2 Daniel D. Billadeau,1,2 and Carlos V. Paya1,3*

Department of Immunology,1 Division of Infectious Diseases,3 Division of Developmental Oncology Research, Mayo Clinic, Rochester, Minnesota 559052

Received 11 October 2002/ Returned for modification 21 November 2002/ Accepted 20 June 2003

NF-{kappa}B is an ubiquitous transcription factor that is a key in the regulation of the immune response and inflammation. T-cell receptor (TCR) cross-linking leads to NF-{kappa}B activation, an I{kappa}B kinase (IKK)-dependent process. However, the upstream kinases that regulate IKK activity following TCR activation remain to be fully characterized. Herein, we demonstrate using genetic analysis, pharmacological inhibition, and RNA interference (RNAi) that the conventional protein kinase C (PKC) isoform PKC{alpha}, but not PKCß1, is required for the activation of the IKK complex following T-cell activation triggered by CD3/CD28 cross-linking. We find that in the presence of Ca2+ influx, the catalytically active PKC{alpha}A25E induces IKK activity and NF-{kappa}B-dependent transcription; which is abrogated following the mutations of two aspartates at positions 246 and 248, which are required for Ca2+ binding to PKC{alpha} and cell membrane recruitment. Kinetic studies reveal that an early phase (1 to 5 min) of IKK activation following TCR/CD28 cross-linking is PKC{alpha} dependent and that a later phase (5 to 25 min) of IKK activation is PKC{theta} dependent. Activation of IKK- and NF-{kappa}B-dependent transcription by PKC{alpha}A25E is abrogated by the PKC{theta} inhibitor rottlerin or the expression of the kinase-inactive form of PKC{theta}. Taken together, our results suggest that PKC{alpha} acts upstream of PKC{theta} to activate the IKK complex and NF-{kappa}B in T lymphocytes following TCR activation.

* Corresponding author. Mailing address: Mayo Clinic, 200 First St. SW, Guggenheim 501, Rochester, MN 55905. Phone: (507) 284-3747. Fax: (507) 284-3757. E-mail: paya{at}mayo.edu.

Molecular and Cellular Biology, October 2003, p. 7068-7081, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.7068-7081.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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