Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways.
Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways.
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DOI：
10.4049/jimmunol.155.10.4685
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发表时间：
1995-11
影响因子：
4.4
通讯作者：
N. Steffan;G. Bren;B. Frantz;M. Tocci;E. O'Neill;C. Payá
中科院分区：
文献类型：
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作者：
N. Steffan;G. Bren;B. Frantz;M. Tocci;E. O'Neill;C. Payá
钙依赖的磷酸酶钙调神经磷酸酶是FK506和CsA的靶标，与PKC诱导的T细胞核因子-kappaB的激活有协同作用。我们已经研究了这种协同作用是否存在于其他类型的细胞中，以及这两种途径导致核因子-kappaB激活的机制(S)。虽然这种协同作用也存在于其他类型的细胞中，但在单核细胞系U937中，钙调神经磷酸酶也足以激活核因子-kappaB。此前我们已经证明，Ca(2+)依赖的通路和PKC依赖的通路通过加速IKBα的降解而协同作用，我们专注于IKBα磷酸化的调节。在T细胞系中，依赖于PKC的信号通路会导致IKBα的磷酸化和不完全降解，而钙依赖的信号通路的共同激活则会加速IKBα的磷酸化并导致其完全降解。单独激活钙依赖通路不会导致Jurkat T或U937细胞中IKBα的磷酸化和/或降解。用选择性的PKC抑制剂GF109203X处理T细胞，可以消除PMA诱导的IKBα的磷酸化/降解，而与激活Ca(2+)依赖的通路无关，但不能阻止由非PKC刺激的肿瘤坏死因子-α诱导的IKBα的磷酸化和降解。与PKC的相互作用相反，Ca(2+)依赖的通路与TNF-α的协同作用不是在IKBα的磷酸化水平上，而是在其降解水平上。这些结果表明，Ca(2+)依赖的途径，包括磷酸酶钙调神经磷酸酶，以细胞特异性的方式参与了对NF-kappaB的调节，并在IKBα的磷酸化和降解水平上与PKC依赖和非依赖的途径协同作用。
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.