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Molecular and Cellular Biology, July 2004, p. 6040-6048, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.6040-6048.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

I{kappa}B Kinase Is an Essential Component of the Tpl2 Signaling Pathway

Michael Waterfield, Wei Jin, William Reiley, Minying Zhang, and Shao-Cong Sun*

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

Received 21 October 2003/ Returned for modification 12 December 2003/ Accepted 8 April 2004

I{kappa}B kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NF-{kappa}B. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKKß in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKKß, but not IKK{alpha}, is required for Tpl2 activation. Moreover, this novel function of IKKß appears to involve phosphorylation and degradation of the Tpl2 inhibitor NF-{kappa}B1/p105. These findings suggest that IKKß exerts its immune-regulatory functions by targeting different downstream signaling pathways.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033. Phone: (717) 531-4164. Fax: (717) 531-6522. E-mail: sxs70{at}psu.edu.

Molecular and Cellular Biology, July 2004, p. 6040-6048, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.6040-6048.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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