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

This Article

	Full Text
	Full Text (PDF)
	Alert me when this article is cited
	Alert me if a correction is posted

Services

	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new issues of the journal
	Download to citation manager
	Reprints and Permissions
	Copyright Information
	Books from ASM Press
	MicrobeWorld

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Yeung, K.
	Articles by Kolch, W.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Yeung, K.
	Articles by Kolch, W.

Previous Article | Next Article

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.

This article has been cited by other articles:

Tsai, M.-C., Shen, L.-F., Kuo, H.-S., Cheng, H., Chak, K.-F. (2008). Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach. Mol. Cell. Proteomics 7: 1668-1687 [Abstract] [Full Text]
Li, H. Z., Wang, Y., Gao, Y., Shao, J., Zhao, X. L., Deng, W. M., Liu, Y. X., Yang, J., Yao, Z. (2008). Effects of Raf Kinase Inhibitor Protein Expression on Metastasis and Progression of Human Epithelial Ovarian Cancer. Mol Cancer Res 6: 917-928 [Abstract] [Full Text]
Chatterjee, D., Sabo, E., Tavares, R., Resnick, M. B. (2008). Inverse Association between Raf Kinase Inhibitory Protein and Signal Transducers and Activators of Transcription 3 Expression in Gastric Adenocarcinoma Patients: Implications for Clinical Outcome. Clin. Cancer Res. 14: 2994-3001 [Abstract] [Full Text]
Al-Mulla, F, Hagan, S, Al-Ali, W, Jacob, S P, Behbehani, A I, Bitar, M S, Dallol, A, Kolch, W (2008). Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability. J. Clin. Pathol. 61: 524-529 [Abstract] [Full Text]
Bonavida, B. (2008). The rituximab-PKC{zeta}/Raf-1/mTOR connection. Blood 111: 5-6 [Full Text]
Robinson, M. J., Beinke, S., Kouroumalis, A., Tsichlis, P. N., Ley, S. C. (2007). Phosphorylation of TPL-2 on Serine 400 Is Essential for Lipopolysaccharide Activation of Extracellular Signal-Regulated Kinase in Macrophages. Mol. Cell. Biol. 27: 7355-7364 [Abstract] [Full Text]
Moffit, J. S., Boekelheide, K., Sedivy, J. M., Klysik, J. (2007). Mice Lacking Raf Kinase Inhibitor Protein-1 (RKIP-1) Have Altered Sperm Capacitation and Reduced Reproduction Rates With a Normal Response to Testicular Injury. J Androl 28: 883-890 [Abstract] [Full Text]
Feng, L., Xie, X., Ding, Q., Luo, X., He, J., Fan, F., Liu, W., Wang, Z., Chen, Y. (2007). Spatial regulation of Raf kinase signaling by RKTG. Proc. Natl. Acad. Sci. USA 104: 14348-14353 [Abstract] [Full Text]
Huang, J., Mahavadi, S., Sriwai, W., Grider, J. R., Murthy, K. S. (2007). Cross-regulation of VPAC2 receptor desensitization by M3 receptors via PKC-mediated phosphorylation of RKIP and inhibition of GRK2. Am. J. Physiol. Gastrointest. Liver Physiol. 292: G867-G874 [Abstract] [Full Text]
Al-Mulla, F., Hagan, S., Behbehani, A. I., Bitar, M. S., George, S. S., Going, J. J., Garcia, J. J. C., Scott, L., Fyfe, N., Murray, G. I., Kolch, W. (2006). Raf Kinase Inhibitor Protein Expression in a Survival Analysis of Colorectal Cancer Patients. JCO 24: 5672-5679 [Abstract] [Full Text]
Rinker-Schaeffer, C. W., O'Keefe, J. P., Welch, D. R., Theodorescu, D. (2006). Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application.. Clin. Cancer Res. 12: 3882-3889 [Full Text]
Rushworth, L. K., Hindley, A. D., O'Neill, E., Kolch, W. (2006). Regulation and role of raf-1/b-raf heterodimerization.. Mol. Cell. Biol. 26: 2262-2272 [Abstract] [Full Text]
Nixon, B., MacIntyre, D. A., Mitchell, L. A., Gibbs, G. M., O'Bryan, M., Aitken, R. J. (2006). The Identification of Mouse Sperm-Surface-Associated Proteins and Characterization of Their Ability to Act as Decapacitation Factors. Biol. Reprod. 74: 275-287 [Abstract] [Full Text]
Konopleva, M., Shi, Y., Steelman, L. S., Shelton, J. G., Munsell, M., Marini, F., McQueen, T., Contractor, R., McCubrey, J. A., Andreeff, M. (2005). Development of a Conditional In vivo Model to Evaluate the Efficacy of Small Molecule Inhibitors for the Treatment of Raf-Transformed Hematopoietic Cells. Cancer Res. 65: 9962-9970 [Abstract] [Full Text]
Hagan, S., Al-Mulla, F., Mallon, E., Oien, K., Ferrier, R., Gusterson, B., Curto Garcia, J. J., Kolch, W. (2005). Reduction of Raf-1 Kinase Inhibitor Protein Expression Correlates with Breast Cancer Metastasis. Clin. Cancer Res. 11: 7392-7397 [Abstract] [Full Text]
Trakul, N., Menard, R. E., Schade, G. R., Qian, Z., Rosner, M. R. (2005). Raf Kinase Inhibitory Protein Regulates Raf-1 but Not B-Raf Kinase Activation. J. Biol. Chem. 280: 24931-24940 [Abstract] [Full Text]
Wang, X., Li, N., Liu, B., Sun, H., Chen, T., Li, H., Qiu, J., Zhang, L., Wan, T., Cao, X. (2004). A Novel Human Phosphatidylethanolamine-binding Protein Resists Tumor Necrosis Factor {alpha}-induced Apoptosis by Inhibiting Mitogen-activated Protein Kinase Pathway Activation and Phosphatidylethanolamine Externalization. J. Biol. Chem. 279: 45855-45864 [Abstract] [Full Text]
Jazirehi, A. R., Vega, M. I., Chatterjee, D., Goodglick, L., Bonavida, B. (2004). Inhibition of the Raf-MEK1/2-ERK1/2 Signaling Pathway, Bcl-xL Down-Regulation, and Chemosensitization of Non-Hodgkin's Lymphoma B Cells by Rituximab. Cancer Res. 64: 7117-7126 [Abstract] [Full Text]
Caesar, R., Blomberg, A. (2004). The Stress-induced Tfs1p Requires NatB-mediated Acetylation to Inhibit Carboxypeptidase Y and to Regulate the Protein Kinase A Pathway. J. Biol. Chem. 279: 38532-38543 [Abstract] [Full Text]
Schuierer, M. M., Bataille, F., Hagan, S., Kolch, W., Bosserhoff, A.-K. (2004). Reduction in Raf Kinase Inhibitor Protein Expression Is Associated with Increased Ras-Extracellular Signal-Regulated Kinase Signaling in Melanoma Cell Lines. Cancer Res. 64: 5186-5192 [Abstract] [Full Text]
Yamazaki, T., Nakano, H., Hayakari, M., Tanaka, M., Mayama, J., Tsuchida, S. (2004). Differentiation Induction of Human Keratinocytes by Phosphatidylethanolamine-binding Protein. J. Biol. Chem. 279: 32191-32195 [Abstract] [Full Text]
Levy, F., Bulet, P., Ehret-Sabatier, L. (2004). Proteomic Analysis of the Systemic Immune Response of Drosophila. Mol. Cell. Proteomics 3: 156-166 [Abstract] [Full Text]
Vander Griend, D. J., Rinker-Schaeffer, C. W. (2004). A New Look at an Old Problem: The Survival and Organ-Specific Growth of Metastases. Sci Signal 2004: pe3-pe3 [Abstract] [Full Text]
Sathe, S. S., Sizemore, N., Li, X., Vithalani, K., Commane, M., Swiatkowski, S. M., Stark, G. R. (2004). Mutant human cells with constitutive activation of NF-{kappa}B. Proc. Natl. Acad. Sci. USA 101: 192-197 [Abstract] [Full Text]
Beinke, S., Deka, J., Lang, V., Belich, M. P., Walker, P. A., Howell, S., Smerdon, S. J., Gamblin, S. J., Ley, S. C. (2003). NF-{kappa}B1 p105 Negatively Regulates TPL-2 MEK Kinase Activity. Mol. Cell. Biol. 23: 4739-4752 [Abstract] [Full Text]
Colanzi, A., Sutterlin, C., Malhotra, V. (2003). RAF1-activated MEK1 is found on the Golgi apparatus in late prophase and is required for Golgi complex fragmentation in mitosis. J. Cell Biol. 161: 27-32 [Abstract] [Full Text]
Corbit, K. C., Trakul, N., Eves, E. M., Diaz, B., Marshall, M., Rosner, M. R. (2003). Activation of Raf-1 Signaling by Protein Kinase C through a Mechanism Involving Raf Kinase Inhibitory Protein. J. Biol. Chem. 278: 13061-13068 [Abstract] [Full Text]
Dhillon, A. S., Meikle, S., Peyssonnaux, C., Grindlay, J., Kaiser, C., Steen, H., Shaw, P. E., Mischak, H., Eychene, A., Kolch, W. (2003). A Raf-1 Mutant That Dissociates MEK/Extracellular Signal-Regulated Kinase Activation from Malignant Transformation and Differentiation but Not Proliferation. Mol. Cell. Biol. 23: 1983-1993 [Abstract] [Full Text]
Hickox, D. M., Gibbs, G., Morrison, J. R., Sebire, K., Edgar, K., Keah, H.-H., Alter, K., Loveland, K. L., Hearn, M. T.W., de Kretser, D. M., O'Bryan, M. K. (2002). Identification of a Novel Testis-Specific Member of the Phosphatidylethanolamine Binding Protein Family, pebp-2. Biol. Reprod. 67: 917-927 [Abstract] [Full Text]
Hindley, A., Kolch, W. (2002). Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases. J. Cell Sci. 115: 1575-1581 [Abstract] [Full Text]
Pnueli, L., Gutfinger, T., Hareven, D., Ben-Naim, O., Ron, N., Adir, N., Lifschitz, E. (2001). Tomato SP-Interacting Proteins Define a Conserved Signaling System That Regulates Shoot Architecture and Flowering. Plant Cell 13: 2687-2702 [Abstract] [Full Text]
Yeung, K. C., Rose, D. W., Dhillon, A. S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W., Sedivy, J. M. (2001). Raf Kinase Inhibitor Protein Interacts with NF-{kappa}B-Inducing Kinase and TAK1 and Inhibits NF-{kappa}B Activation. Mol. Cell. Biol. 21: 7207-7217 [Abstract] [Full Text]
Kroslak, T., Koch, T., Kahl, E., Hollt, V. (2001). Human Phosphatidylethanolamine-binding Protein Facilitates Heterotrimeric G Protein-dependent Signaling. J. Biol. Chem. 276: 39772-39778 [Abstract] [Full Text]
Monick, M. M., Staber, J. M., Thomas, K. W., Hunninghake, G. W. (2001). Respiratory Syncytial Virus Infection Results in Activation of Multiple Protein Kinase C Isoforms Leading to Activation of Mitogen-Activated Protein Kinase. J. Immunol. 166: 2681-2687 [Abstract] [Full Text]
Gupta, S., Plattner, R., Der, C. J., Stanbridge, E. J. (2000). Dissection of Ras-Dependent Signaling Pathways Controlling Aggressive Tumor Growth of Human Fibrosarcoma Cells: Evidence for a Potential Novel Pathway. Mol. Cell. Biol. 20: 9294-9306 [Abstract] [Full Text]
Kuboki, Y., Ito, M., Takamatsu, N., Yamamoto, K.-i., Shiba, T., Yoshioka, K. (2000). A Scaffold Protein in the c-Jun NH2-terminal Kinase Signaling Pathways Suppresses the Extracellular Signal-regulated Kinase Signaling Pathways. J. Biol. Chem. 275: 39815-39818 [Abstract] [Full Text]
Hengst, U., Albrecht, H., Hess, D., Monard, D. (2001). The Phosphatidylethanolamine-binding Protein Is the Prototype of a Novel Family of Serine Protease Inhibitors. J. Biol. Chem. 276: 535-540 [Abstract] [Full Text]

J. Bacteriol.	J. Virol.	Eukaryot. Cell

Microbiol. Mol. Biol. Rev.	Clin. Vaccine Immunol.	All ASM Journals