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Molecular and Cellular Biology, August 2002, p. 5962-5974, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5962-5974.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Akt-Dependent Phosphorylation Specifically Regulates Cot Induction of NF-B-Dependent Transcription

Department of Medicine,¹ The Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143,² Max Planck Institute of Psychiatry, Molecular, Cellular, Clinical Proteomics, D-80804 Munich, Germany³

Received 13 December 2001/ Returned for modification 25 March 2002/ Accepted 4 June 2002

The Akt (or protein kinase B) and Cot (or Tpl-2) serine/threonine kinases are associated with cellular transformation. These kinases have also been implicated in the induction of NF-B-dependent transcription. As a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, Cot can also activate MAP kinase signaling pathways that target AP-1 and NFAT family transcription factors. Here we show that Akt and Cot physically associate and functionally cooperate. Akt appears to function upstream of Cot, as Akt can enhance Cot induction of NF-B-dependent transcription, and dominant-negative Cot blocks the activation of this element by Akt. Furthermore, deletion analysis shows that binding to Akt is critical for Cot function. The regulation of NF-B-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400), near the carboxy terminus of Cot. However, phosphorylation at this site is not required for Cot kinase activity or AP-1 induction, suggesting it specifically regulates Cot effector function at the level of the NF-B pathway. Mutation of S400 in Cot does indeed abolish its ability to activate IB-kinase (IKK) complexes, but paradoxically it allows for increased Cot association with the IKK complex. This mutated form of Cot also acts as a dominant negative for T-cell antigen receptor/CD28- or Akt/phorbol myristate acetate-induced NF-B induction, while having relatively little effect on tumor necrosis factor induction of NF-B. These findings suggest that the activation of different signaling pathways by MAP3Ks may be regulated separately and may provide evidence for how such discrimination by one member of this kinase family occurs.

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