The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation

Michael Karin

doi:10.1074/jbc.274.39.27339

September 1, 1999Journal of Biological ChemistryOpen Access

The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation

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Key Points

To review the structural architecture, enzymatic mechanisms, and physiological roles of the IκB kinase complex and its distinct subunits in directing NF-κB activation.
Synthesized molecular, structural, and biochemical evidence characterizing the ternary NF-κB and IκB complex and the multiprotein IKK kinase assembly.
Analyzed in vitro phosphorylation and ubiquitination reconstitution assays targeting conserved N-terminal serine residues (Ser-32 and Ser-36) of IκBα.
Evaluated comparative genetic knockout studies in mice to distinguish the non-redundant biological functions of IKKα and IKKβ.
Stimulus-dependent phosphorylation of IκB N-terminal serines by the IKK complex functions as the sole regulated step triggering recognition and polyubiquitination by an F-box/WD-repeat E3 ligase.
IKKβ acts as the indispensable catalytic engine for cytokine-induced NF-κB activation, whereas IKKα regulates morphogenetic pathways independent of classic inflammatory signaling.
Autophosphorylation of carboxyl-terminal serine clusters within IKK subunits confers intrinsic negative feedback to terminate kinase activity and prevent hyperinflammation.

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Implication

Mechanistic review uncovers the phosphorylation and degradation cascade of IκB in mammalian cells, highlighting IκB kinase as a critical checkpoint for inflammatory responses.

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Michael Karin (1999) studied this question.

synapsesocial.com/papers/6a1548f6eecc40546481f595 https://doi.org/10.1074/jbc.274.39.27339

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The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation

Key Points

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The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation

Key Points

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