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Molecular and Cellular Biology, December 1998, p. 7336-7343, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Coordinate Regulation of Ikappa B Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-kappa B-Inducing Kinase

Shino Nemoto,1 Joseph A. DiDonato,2 and Anning Lin1,*

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294,1 and Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441952

Received 1 May 1998/Returned for modification 5 June 1998/Accepted 16 September 1998

Ikappa B kinases (IKKalpha and IKKbeta ) are key components of the IKK complex that mediates activation of the transcription factor NF-kappa B in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-kappa B-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-alpha ) and interleukin-1 and can potentiate the stimulatory effect of TNF-alpha on IKK and NF-kappa B activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-alpha . MEKK1 interacts with and stimulates the activities of both IKKalpha and IKKbeta in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.

* Corresponding author. Mailing address: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294. Phone: (205) 975-9225. Fax: (205) 934-1775. E-mail: lin{at}vh.path.uab.edu.

Molecular and Cellular Biology, December 1998, p. 7336-7343, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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