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J. Biol. Chem., Vol. 277, Issue 27, 24331-24339, July 5, 2002

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Regulation of IB Kinase (IKK)/NEMO Function by IKK-mediated Phosphorylation^*

Shashi Prajapati and Richard B. Gaynor

From the Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The IB kinase (IKK) complex includes the catalytic components IKK and IKK in addition to the scaffold protein IKK/NEMO. Increases in the activity of the IKK complex result in the phosphorylation and subsequent degradation of IB and the activation of the NF-B pathway. Recent data indicate that the constitutive activation of the NF-B pathway by the human T-cell lymphotrophic virus, type I, Tax protein leads to enhanced phosphorylation of IKK/NEMO by IKK. To address further the significance of IKK-mediated phosphorylation of IKK/NEMO, we determined the sites in IKK/NEMO that were phosphorylated by IKK, and we assayed whether IKK/NEMO phosphorylation was involved in modulating IKK activity. IKK/NEMO is rapidly phosphorylated following treatment of cells with stimuli such as tumor necrosis factor- and interleukin-1 that activate the NF-B pathway. By using both in vitro and in vivo assays, IKK was found to phosphorylate IKK/NEMO predominantly in its carboxyl terminus on serine residue 369 in addition to sites in the central region of this protein. Surprisingly, mutation of these carboxyl-terminal serine residues increased the ability of IKK/NEMO to stimulate IKK kinase activity. These results indicate that the differential phosphorylation of IKK/NEMO by IKK and perhaps other kinases may be important in regulating IKK activity.

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