Mechanism of Suppression of the Raf/MEK/Extracellular Signal-Regulated Kinase Pathway by the Raf Kinase Inhibitor Protein

doi:10.1128/MCB.20.9.3079-3085.2000

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Molecular and Cellular Biology, May 2000, p. 3079-3085, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mechanism of Suppression of the Raf/MEK/Extracellular Signal-Regulated Kinase Pathway by the Raf Kinase Inhibitor Protein

Kam Yeung,¹ Petra Janosch,² Brian McFerran,² David W. Rose,³ Harald Mischak,⁴ John M. Sedivy,¹^,^* and Walter Kolch²^,^*

Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912¹; Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, Glasgow G61 1BD, United Kingdom²; Department of Medicine and Whittier Diabetes Program, University of California San Diego, La Jolla, California 92093-0673³; and Abt. Nephrologie, Medizinische Hochschule Hannover, D-0625 Hannover, Germany⁴

Received 7 October 1999/Returned for modification 4 November 1999/Accepted 18 February 2000

We have recently identified the Raf kinase inhibitor protein (RKIP) as a physiological endogenous inhibitor of the Raf-1/MEK/extracellularsignal-regulated kinase (ERK) pathway. RKIP interfered with MEKphosphorylation and activation by Raf-1, resulting in the suppressionof both Raf-1-induced transformation and AP-1-dependent transcription.Here we report the molecular mechanism of RKIP's inhibitory function.RKIP can form ternary complexes with Raf-1, MEK, and ERK. However,whereas MEK and ERK can simultaneously associate with RKIP, Raf-1binding to RKIP and that of MEK are mutually exclusive. RKIP isable to dissociate a Raf-1-MEK complex and behaves as a competitiveinhibitor of MEK phosphorylation. Mapping of the binding domainsshowed that MEK and Raf-1 bind to overlapping sites in RKIP, whereasMEK and RKIP associate with different domains in Raf-1, and Raf-1and RKIP bind to different sites in MEK. Both the Raf-1 and theMEK binding sites in RKIP need to be destroyed in order to relieveRKIP-mediated suppression of the Raf-1/MEK/ERK pathway, indicatingthat binding of either Raf-1 or MEK is sufficient for inhibition.The properties of RKIP reveal the specific sequestration of interactingcomponents as a novel motif in the cell's repertoire for the regulationof signalingpathways.

^* Corresponding author. Mailing address for Walter Kolch: The Beatson Institute for Cancer Research, CRC Beatson Laboratories,Garscube Estate, Switchback Rd., Bearsden, Glasgow G61 1BD, UnitedKingdom. Phone: 0044-141-330 3983. Fax: 0044-141-943 0372. E-mail:wkolch{at}beatson.gla.ac.uk. Mailing address for John M. Sedivy:Department of Molecular Biology, Cell Biology and Biochemistry,Brown University, Brown St., Providence, R.I. 02912. Phone: (401)863-2937. Fax: (401) 863-1201. E-mail: john_sedivy{at}brown.edu.

Molecular and Cellular Biology, May 2000, p. 3079-3085, Vol. 20, No. 9
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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