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首页> 外文期刊>Molecular and Cellular Biology >Activation of I#kappa#B Kinase #beta# by Protein Kinase C Isoforms
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Activation of I#kappa#B Kinase #beta# by Protein Kinase C Isoforms

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The atypical protein kinase C (PKC) isotypes (#lambda#/#iota#PKC and #zeta#PKC) have been shown to be critically involved in important cell functions such as proliferation and survival. Previous studies have demonstrated that the atypical PKCs are stimulated by tumor necrosis factor alpha (TNF-#alpha#) and are required for the activation of NF-#kappa#B by this cytokine through a mechanism that most probably involves the phosphorylation of I#kappa#B. The inability of these PKC isotypes to directly phosphorylate I#kappa#B led to the hypothesis that #zeta#PKC may use a putative I#kappa#B kinase to functionally inactivate I#kappa#B. Recently several groups have molecularly characterized and cloned two I#kappa#B kinases (IKK#alpha# and IKK#beta#) which phosphorylate the residues in the I#kappa#B molecule that serve to target it for ubiquitination and degradation. In this study we have addressed the possibility that different PKCs may control NF-#kappa#B through the activation of the IKKs. We report here that #alpha#PKC as well as the atypical PKCs bind to the IKKs in vitro and in vivo. In addition, overexpression of #zeta#PKC positively modulates IKK#beta# activity but not that of IKK#alpha#, whereas the transfection of a #zeta#PKC dominant negative mutant severely impairs the activation of IKK#beta# but not IKK#alpha# in TNF-#alpha#-stimulated cells. We also show that cell stimulation with phorbol 12-myristate 13-acetate activates IKK#beta#, which is entirely dependent on the activity of #alpha#PKC but not that of the atypical isoforms. In contrast, the inhibition of #alpha#PKC does not affect the activation of IKK#beta# by TNF-#alpha#. Interestingly, recombinant active #zeta#PKC and #alpha#PKC are able to stimulate in vitro the activity of IKK#beta# but not that of IKK#alpha#. In addition, evidence is presented here that recombinant #zeta#PKC directly phosphorylates IKK#beta# in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-#kappa#B pathway at the level of IKK#beta# activation and IkB degradation.

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