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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/extracellular signal-regulated kinase (ERK) pathway. RKIP interfered with MEK phosphorylation and activation by Raf-1, resulting in the suppression of 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-1 binding to RKIP and that of MEK are mutually exclusive. RKIP is able to dissociate a Raf-1-MEK complex and behaves as a competitive inhibitor of MEK phosphorylation. Mapping of the binding domains showed that MEK and Raf-1 bind to overlapping sites in RKIP, whereas MEK and RKIP associate with different domains in Raf-1, and Raf-1 and RKIP bind to different sites in MEK. Both the Raf-1 and the MEK binding sites in RKIP need to be destroyed in order to relieve RKIP-mediated suppression of the Raf-1/MEK/ERK pathway, indicating that binding of either Raf-1 or MEK is sufficient for inhibition. The properties of RKIP reveal the specific sequestration of interacting components as a novel motif in the cell's repertoire for the regulation of signaling pathways.

* Corresponding author. Mailing address for Walter Kolch: The Beatson Institute for Cancer Research, CRC Beatson Laboratories, Garscube Estate, Switchback Rd., Bearsden, Glasgow G61 1BD, United Kingdom. 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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