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Molecular and Cellular Biology, July 2003, p. 4739-4752, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.4739-4752.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B1 p105 Negatively Regulates TPL-2 MEK Kinase Activity

S. Beinke,1 J. Deka,2 V. Lang,1 M. P. Belich,1 P. A. Walker,2 S. Howell,2 S. J. Smerdon,2* S. J. Gamblin,2 and S. C. Ley1*

Divisions of Immune Cell Biology,1 Protein Structure, National Institute for Medical Research, London NW7 1AA, United Kingdom2

Received 4 February 2003/ Returned for modification 10 March 2003/ Accepted 18 April 2003

Activation of the oncogenic potential of the MEK kinase TPL-2 (Cot) requires deletion of its C terminus. This mutation also weakens the interaction of TPL-2 with NF-{kappa}B1 p105 in vitro, although it is unclear whether this is important for the activation of TPL-2 oncogenicity. It is demonstrated here that TPL-2 stability in vivo relies on its high-affinity, stoichiometric association with NF-{kappa}B1 p105. Formation of this complex occurs as a result of two distinct interactions. The TPL-2 C terminus binds to a region encompassing residues 497 to 534 of p105, whereas the TPL-2 kinase domain interacts with the p105 death domain. Binding to the p105 death domain inhibits TPL-2 MEK kinase activity in vitro, and this inhibition is significantly augmented by concomitant interaction of the TPL-2 C terminus with p105. In cotransfected cells, both interactions are required for inhibition of TPL-2 MEK kinase activity and, consequently, the catalytic activity of a C-terminally truncated oncogenic mutant of TPL-2 is not affected by p105. Thus, in addition to its role as a precursor for p50 and cytoplasmic inhibitor of NF-{kappa}B, p105 is a negative regulator of TPL-2. Insensitivity of C-terminally truncated TPL-2 to this regulatory mechanism is likely to contribute to its ability to transform cells.

* Corresponding author. Mailing address: Divisions of Immune Cell Biology (S.C.L.) and Protein Structure (S.J.S.), National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA London, United Kingdom. Phone: 44-8816-2463. Fax: 44-8906-4477. E-mail for S. C. Ley: sley{at}nimr.mrc.ac.uk. E-mail for S. J. Smerdon: ssmerdo{at}nimr.mrc.ac.uk.

Molecular and Cellular Biology, July 2003, p. 4739-4752, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.4739-4752.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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