DOI: 10.1073/pnas.95.16.9319. MEKK1 activates both IκB kinase α and IκB kinase β

MEKK1 activates both IκB kinase α and IκB kinase β

10.1073/pnas.95.16.9319

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

A critical step in the signal-induced activation of the transcription factor NF-κB is the site-specific phosphorylation of its inhibitor, IκB, that targets the latter for degradation by the ubiquitin–proteasome pathway. We have previously shown that mitogen-activated protein kinase/ERK kinase kinase 1 (MEKK1) can induce both this site-specific phosphorylation of IκBα at Ser-32 and Ser-36 in vivo and the activity of a high molecular weight IκB kinase complex in vitro . Subsequently, others have identified two proteins, IκB kinase α (IKK-α) and IκB kinase β (IKK-β), that are present in a tumor necrosis factor α-inducible, high molecular weight IκB kinase complex. These kinases are believed to directly phosphorylate IκB based on the examination of the kinase activities of IKK immunoprecipitates, but more rigorous proof of this has yet to be demonstrated. We show herein that recombinant IKK-α and IKK-β can, in fact, directly phosphorylate IκBα at Ser-32 and Ser-36, as well as homologous residues in IκBβ in vitro , and thus are bona fide IκB kinases. We also show that MEKK1 can induce the activation of both IKK-α and IKK-β in vivo . Finally, we show that IKK-α is present in the MEKK1-inducible, high molecular weight IκB kinase complex and treatment of this complex with MEKK1 induces phosphorylation of IKK-α in vitro . We conclude that IKK-α and IKK-β can mediate the NF-κB-inducing activity of MEKK1.

Bibliography

Lee, F. S., Peters, R. T., Dang, L. C., & Maniatis, T. (1998). MEKK1 activates both IÎºB kinase Î± and IÎºB kinase Î². Proceedings of the National Academy of Sciences, 95(16), 9319â9324.

Authors 4

Frank S. Lee (first)
Robert T. Peters (additional)
Luan C. Dang (additional)
Tom Maniatis (additional)

References 33 Referenced 322

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:39 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 4:37 p.m.)
Indexed	2 months ago (June 26, 2025, 2:42 p.m.)
Issued	27 years ago (Aug. 4, 1998)
Published	27 years ago (Aug. 4, 1998)
Published Online	27 years ago (Aug. 4, 1998)
Published Print	27 years ago (Aug. 4, 1998)

Funders 0

None

BibTeX

@article{Lee_1998, title={MEKK1 activates both IκB kinase α and IκB kinase β}, volume={95}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.95.16.9319}, DOI={10.1073/pnas.95.16.9319}, number={16}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Lee, Frank S. and Peters, Robert T. and Dang, Luan C. and Maniatis, Tom}, year={1998}, month=aug, pages={9319–9324} }

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  "abstract": "<jats:p>\n            A critical step in the signal-induced activation of the transcription factor NF-\u03baB is the site-specific phosphorylation of its inhibitor, I\u03baB, that targets the latter for degradation by the ubiquitin\u2013proteasome pathway. We have previously shown that mitogen-activated protein kinase/ERK kinase kinase 1 (MEKK1) can induce both this site-specific phosphorylation of I\u03baB\u03b1 at Ser-32 and Ser-36\n            <jats:italic>in vivo</jats:italic>\n            and the activity of a high molecular weight I\u03baB kinase complex\n            <jats:italic>in vitro</jats:italic>\n            . Subsequently, others have identified two proteins, I\u03baB kinase \u03b1 (IKK-\u03b1) and I\u03baB kinase \u03b2 (IKK-\u03b2), that are present in a tumor necrosis factor \u03b1-inducible, high molecular weight I\u03baB kinase complex. These kinases are believed to directly phosphorylate I\u03baB based on the examination of the kinase activities of IKK immunoprecipitates, but more rigorous proof of this has yet to be demonstrated. We show herein that recombinant IKK-\u03b1 and IKK-\u03b2 can, in fact, directly phosphorylate I\u03baB\u03b1 at Ser-32 and Ser-36, as well as homologous residues in I\u03baB\u03b2\n            <jats:italic>in vitro</jats:italic>\n            , and thus are bona fide I\u03baB kinases. We also show that MEKK1 can induce the activation of both IKK-\u03b1 and IKK-\u03b2\n            <jats:italic>in vivo</jats:italic>\n            . Finally, we show that IKK-\u03b1 is present in the MEKK1-inducible, high molecular weight I\u03baB kinase complex and treatment of this complex with MEKK1 induces phosphorylation of IKK-\u03b1\n            <jats:italic>in vitro</jats:italic>\n            . We conclude that IKK-\u03b1 and IKK-\u03b2 can mediate the NF-\u03baB-inducing activity of MEKK1.\n          </jats:p>",
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