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J. Biol. Chem., Vol. 280, Issue 30, 27759-27768, July 29, 2005

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Pellino3 Is a Novel Upstream Regulator of p38 MAPK and Activates CREB in a p38-dependent Manner^*

Marion P. Butler, Jennifer A. Hanly, and Paul N. Moynagh

From the Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

Engagement of the interleukin-1 (IL-1) and Toll-like receptors triggers mitogen-activated protein kinase (MAPK) pathways and activation of transcription factors such as NFB and AP-1. Recent studies have identified members of the Pellino protein family as novel mediators in mediating activation of these pathways. However, no evidence has been presented to date to suggest a role for the Pellino proteins in activation of the p38 MAPK pathway. We demonstrate herein that Pellino3 is a strong activator of p38 MAPK. RNA interference was used to reveal a physiological role for Pellino3 in the IL-1 pathway leading to activation of p38 MAPK. A series of N-terminal truncation and point mutants of Pellino3 were generated and tested for their ability to activate p38 MAPK in an effort to map sites of protein interaction important for p38 MAPK activation. In this way we show that the binding of Pellino3 to IL-1 receptor-associated kinase 1 coincides with its ability to promote p38 MAPK activation. TRAF-6 and transforming growth factor--activating kinase 1 are shown to act as downstream mediators of the activation of p38 MAPK by Pellino3. Finally we confirm the functional consequences of the activation of p38 MAPK by Pellino3 by demonstrating that Pellino3 promotes translocation of the p38 substrate, MAPK-activated protein kinase2, from the nucleus to the cytoplasm and activates the transcription factor CREB in a p38 MAPK-dependent manner. Our study not only identifies Pellino3 as a novel upstream regulator of the p38 MAPK pathway but also probes the mechanistic basis underlying the ability of Pellino3 to promote activation of this pathway.

Received for publication, January 21, 2005 , and in revised form, May 11, 2005.

^* This work was supported by funding from the Health Research Board of Ireland, Higher Education Authority of Ireland, and European Biotechnology 5th Framework programme (Contracts QLG1-CT-1999-00549 and QLK3-CT-2000-00270) The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Tel.: 353-1-716-6761; Fax: 353-1-269-2749; E-mail: P.Moynagh{at}ucd.ie.

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