Raf kinase inhibitor protein interacts with NF-κB-inducing kinase and TAK1 and inhibits NF-κ13 activation

被引:318
作者
Yeung, KC
Rose, DW
Dhillon, AS
Yaros, D
Gustafsson, M
Chatterjee, D
McFerran, B
Wyche, J
Kolch, W
Sedivy, JM
机构
[1] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA
[2] Univ Calif San Diego, Whittier Diabet Program, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[4] CRC, Beatson Labs, Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland
关键词
D O I
10.1128/MCB.21.21.7207-7217.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Raf kinase inhibitor protein (RKIP) acts as a negative regulator of the mitogen-activated protein (MAP) kinase (MAPK) cascade initiated by Raf-1. RKIP inhibits the phosphorylation of MAP/extracellular signal-regulated kinase 1 (MEK1) by Raf-1 by disrupting the interaction between these two kinases. We show here that RKIP also antagonizes the signal transduction pathways that mediate the activation of the transcription factor nuclear factor kappa B (NF-kappaB) in response to stimulation with tumor necrosis factor alpha (TNF-alpha) or interleukin 1 beta. Modulation of RKIP expression levels affected NF-kappaB signaling independent of the MAPK pathway. Genetic epistasis analysis involving the ectopic expression of kinases acting in the NF-kappaB pathway indicated that RKIP acts upstream of the kinase complex that mediates the phosphorylation and inactivation of the inhibitor of NF-kappaB (I kappaB). In vitro kinase assays showed that RKIP antagonizes the activation of the I kappaB kinase (IKK) activity elicited by TNF-alpha. RKIP physically interacted with four kinases of the NF-KB activation pathway, NF-kappaB-inducing kinase, transforming growth factor beta-activated kinase 1, IKK alpha, and IKK beta. This mode of action bears striking similarities to the interactions of RKIP with Raf-1 and MEK1 in the MAPK pathway. Emerging data from diverse organisms suggest that RKIP and RKIP-related proteins represent a new and evolutionarily highly conserved family of protein kinase regulators. Since the MAPK and NF-kappaB pathways have physiologically distinct roles, the function of RKIP may be, in part, to coordinate the regulation of these pathways.
引用
收藏
页码:7207 / 7217
页数:11
相关论文
共 79 条
[51]   The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway [J].
Ninomiya-Tsuji, J ;
Kishimoto, K ;
Hiyama, A ;
Inoue, J ;
Cao, ZD ;
Matsumoto, K .
NATURE, 1999, 398 (6724) :252-256
[52]   ASK1 is essential for JNK/SAPK activation by TRAF2 [J].
Nishitoh, H ;
Saitoh, M ;
Mochida, Y ;
Takeda, K ;
Nakano, H ;
Rothe, M ;
Miyazono, K ;
Ichijo, H .
MOLECULAR CELL, 1998, 2 (03) :389-395
[53]   Oncogenic Ras enhances NF-κB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated protein kinase signaling pathways [J].
Norris, JL ;
Baldwin, AS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (20) :13841-13846
[54]  
OPIPARI AW, 1992, J BIOL CHEM, V267, P12424
[55]  
Ozes ON, 1999, NATURE, V401, P82
[56]   PRODUCTION OF HIGH-TITER HELPER-FREE RETROVIRUSES BY TRANSIENT TRANSFECTION [J].
PEAR, WS ;
NOLAN, GP ;
SCOTT, ML ;
BALTIMORE, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (18) :8392-8396
[57]   MEMBERS OF A FAMILY OF DROSOPHILA PUTATIVE ODORANT-BINDING PROTEINS ARE EXPRESSED IN DIFFERENT SUBSETS OF OLFACTORY HAIRS [J].
PIKIELNY, CW ;
HASAN, G ;
ROUYER, F ;
ROSBASH, M .
NEURON, 1994, 12 (01) :35-49
[58]   NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase [J].
Pomerantz, JL ;
Baltimore, D .
EMBO JOURNAL, 1999, 18 (23) :6694-6704
[59]   Identification and characterization of an I kappa B kinase [J].
Regnier, CH ;
Song, HY ;
Gao, X ;
Goeddel, DV ;
Cao, ZD ;
Rothe, M .
CELL, 1997, 90 (02) :373-383
[60]   TFS1 - A SUPPRESSOR OF CDC25 MUTATIONS IN SACCHAROMYCES-CEREVISIAE [J].
ROBINSON, LC ;
TATCHELL, K .
MOLECULAR & GENERAL GENETICS, 1991, 230 (1-2) :241-250