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Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways.

N M Steffan, G D Bren, B Frantz, M J Tocci, E A O'Neill and C V Paya
J Immunol November 15, 1995, 155 (10) 4685-4691;
N M Steffan
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G D Bren
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B Frantz
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M J Tocci
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E A O'Neill
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C V Paya
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Abstract

The Ca(2+)-dependent phosphatase calcineurin, a target of FK506 and CsA, synergizes with PKC-induced activation of nuclear factor (NF)-kappa B in T cell lines. We have investigated whether this synergy is present in other cell types and the mechanism(s) by which these two pathways lead to NF-kappa B activation. While this synergy is present in other cell types, in the monocytic cell line U937 calcineurin is also sufficient to activate NF-kappa B. Having previously shown that Ca(2+)- and PKC-dependent pathways synergize by accelerating the degradation of IkB alpha, we focused on the regulation of IkB alpha phosphorylation. While PKC-dependent pathways sequentially result in the phosphorylation and in an incomplete degradation of IkB alpha in T cell lines, co-activation of Ca(2+)-dependent pathways accelerates the rate of IkB alpha phosphorylation and results in its complete degradation. Activation of Ca(2+)-dependent pathways alone do not result in the phosphorylation and/or degradation of IkB alpha in Jurkat T or in U937 cells. Treatment of T cells with the selective PKC inhibitor GF109203X abrogates the PMA-induced IkB alpha phosphorylation/degradation irrespective of activation of Ca(2+)-dependent pathways, but not the phosphorylation and degradation of IkB alpha induced by TNF-alpha, a PKC-independent stimulus. Contrary to the interaction with PKC, Ca(2+)-dependent pathways synergize with TNF-alpha not at the level of IkB alpha phosphorylation, but at the level of its degradation. These results indicate that Ca(2+)-dependent pathways, including the phosphatase calcineurin, participate in the regulation of NF-kappa B in a cell specific fashion and synergize with PKC-dependent and -independent pathways at the level of IkB alpha phosphorylation and degradation.

  • Copyright © 1995 by American Association of Immunologists

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The Journal of Immunology
Vol. 155, Issue 10
15 Nov 1995
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Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways.
N M Steffan, G D Bren, B Frantz, M J Tocci, E A O'Neill, C V Paya
The Journal of Immunology November 15, 1995, 155 (10) 4685-4691;

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Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways.
N M Steffan, G D Bren, B Frantz, M J Tocci, E A O'Neill, C V Paya
The Journal of Immunology November 15, 1995, 155 (10) 4685-4691;
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Print ISSN 0022-1767        Online ISSN 1550-6606