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J. Biol. Chem., Vol. 282, Issue 44, 32311-32319, November 2, 2007

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Signal Responsiveness of IB Kinases Is Determined by Cdc37-assisted Transient Interaction with Hsp90^*

From the Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany

The IB kinase (IKK) holocomplex, containing the kinases IKK, IKK, and the scaffold NEMO (NF-B essential modifier), mediates activation of NF-B by numerous physiological stimuli. Heat shock protein 90 (Hsp90) and the co-chaperone Cdc37 have been indicated as additional subunits, but their specific functions in signal transduction are indistinct. Using an RNA interference approach, we demonstrate that Cdc37 recruits Hsp90 to the IKK complex in a transitory manner, preferentially via IKK. Binding is conferred by N-terminal as well as C-terminal residues of Cdc37. Cdc37 is essential for the maturation of de novo synthesized IKKs into enzymatically competent kinases but not for assembly of an IKK holocomplex. Mature IKKs, T-loop-phosphorylated after stimulation either by receptor-mediated signaling or upon DNA damage, further require Hsp90-Cdc37 to generate an activated state. Thus, the present data denote Hsp90-Cdc37 as a transiently acting essential regulatory component of IKK signaling.

Received for publication, July 13, 2007 , and in revised form, August 28, 2007.

^* This work was supported in part by grants from the European Union (Europäischer Fonds für regionale Entwicklung) and Deutsche Forsch-ungsgemeinschaft (to C. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ These authors contributed equally to this work.

² Present address: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, United Kingdom.

³ To whom correspondence should be addressed. Tel.: 49-30-9604-3816; Fax: 49-30-9604-3866; E-mail: scheidereit{at}mdc-berlin.de.

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