Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Role of mitogen-activated protein kinase kinase kinases in signal integration

Abstract

Mitogen-activated protein kinases (MAPKs) are members of a dynamic protein kinase network through which diverse stimuli regulate the spatio-temporal activities of complex biological systems. MAPKs regulate critical cellular functions required for homeostasis such as the expression of cytokines and proteases, cell cycle progression, cell adherence, motility and metabolism. MAPKs therefore influence cell proliferation, differentiation, survival, apoptosis and development. In vertebrates, five MAPK families are regulated by MAPK kinase kinase-MAPK kinase-MAPK (MKKK-MKK-MAPK) phosphorelay systems. There are at least 20 MKKKs that selectively phosphorylate and activate different combinations of the seven MKKs, resulting in a specific activation profile of members within the five MAPK families. MKKKs are differentially activated by upstream stimuli including cytokines, antigens, toxins and stress insults providing a mechanism to integrate the activation of different MAPKs with the cellular response to each stimulus. Thus, MKKKs can be considered as ‘signaling hubs’ that regulate the specificity of MAPK activation. In this review, we describe how the MKKK ‘hub’ function regulates the specificity of MAPK activation, highlighting MKKKs as targets for therapeutic intervention in cancer and other diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Abell AN, Johnson GL . (2005). MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J Biol Chem 280: 35793–35796.

    Article  CAS  PubMed  Google Scholar 

  • Abell AN, Rivera-Perez JA, Cuevas BD, Uhlik MT, Sather S, Johnson NL et al. (2005). Ablation of MEKK4 kinase activity causes neurulation and skeletal patterning defects in the mouse embryo. Mol Cell Biol 25: 8948–8959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akaike M, Che W, Marmarosh NL, Ohta S, Osawa M, Ding B et al. (2004). The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extracellular signal-regulated kinase 5 and PPARgamma1 transcriptional activation: involvement in flow-induced PPARgamma activation in endothelial cells. Mol Cell Biol 24: 8691–8704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beeram M, Patnaik A, Rowinsky EK . (2005). Raf: a strategic target for therapeutic development against cancer. J Clin Oncol 23: 6771–6790.

    Article  CAS  PubMed  Google Scholar 

  • Blank JL, Gerwins P, Elliott EM, Sather S, Johnson GL . (1996). Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J Biol Chem 271: 5361–5368.

    Article  CAS  PubMed  Google Scholar 

  • Brancho D, Ventura JJ, Jaeschke A, Doran B, Flavell RA, Davis RJ . (2005). Role of MLK3 in the regulation of mitogen-activated protein kinase signaling cascades. Mol Cell Biol 25: 3670–3681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown K, Vial SC, Dedi N, Long JM, Dunster NJ, Cheetham GM . (2005). Structural basis for the interaction of TAK1 kinase with its activating protein TAB1. J Mol Biol 354: 1013–1020.

    Article  CAS  PubMed  Google Scholar 

  • Camarero G, Tyrsin OY, Xiang C, Pfeiffer V, Pleiser S, Wiese S et al. (2006). Cortical migration defects in mice expressing A-RAF from the B-RAF locus. Mol Cell Biol 26: 7103–7115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro A, Peter M, Lorca T, Mandart E . (2001). c-Mos and cyclin B/cdc2 connections during Xenopus oocyte maturation. Biol Cell 93: 15–25.

    Article  CAS  PubMed  Google Scholar 

  • Chen M, Cooper JA . (1995). Ser-3 is important for regulating Mos interaction with and stimulation of mitogen-activated protein kinase kinase. Mol Cell Biol 15: 4727–4734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Z, Hutchison M, Cobb MH . (1999). Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain. J Biol Chem 274: 28803–28807.

    Article  CAS  PubMed  Google Scholar 

  • Chi H, Sarkisian MR, Rakic P, Flavell RA . (2005). Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proc Natl Acad Sci USA 102: 3846–3851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho J, Melnick M, Solidakis GP, Tsichlis PN . (2005). Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Ikappa-B kinase-beta-dependent pathway and is required for Tpl2 activation by external signals. J Biol Chem 280: 20442–20448.

    Article  CAS  PubMed  Google Scholar 

  • Christoforidou AV, Papadaki HA, Margioris AN, Eliopoulos GD, Tsatsanis C . (2004). Expression of the Tpl2/Cot oncogene in human T-cell neoplasias. Mol Cancer 3: 34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cuevas BD, Abell AN, Witowsky JA, Yujiri T, Johnson NL, Kesavan K et al. (2003). MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. EMBO J 22: 3346–3355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuevas BD, Uhlik MT, Garrington TP, Johnson GL . (2005). MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability. Oncogene 24: 801–809.

    Article  CAS  PubMed  Google Scholar 

  • Cuevas BD, Winter-Vann AM, Johnson NL, Johnson GL . (2006). MEKK1 controls matrix degradation and tumor cell dissemination during metastasis of polyoma middle-T driven mammary cancer. Oncogene 25: 4998–5010.

    Article  CAS  PubMed  Google Scholar 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417: 949–954.

    Article  CAS  PubMed  Google Scholar 

  • Deng M, Chen WL, Takatori A, Peng Z, Zhang L, Mongan M et al. (2006). A role for the mitogen-activated protein kinase kinase kinase 1 in epithelial wound healing. Mol Biol Cell 17: 3446–3455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD et al. (2005). Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17: 215–224.

    Article  CAS  PubMed  Google Scholar 

  • Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH et al. (2000). TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103: 1071–1083.

    Article  CAS  PubMed  Google Scholar 

  • Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R et al. (2006). Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer 95: 581–586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eliopoulos AG, Wang CC, Dumitru CD, Tsichlis PN . (2003). Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40. EMBO J 22: 3855–3864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fanger GR, Johnson NL, Johnson GL . (1997). MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. EMBO J 16: 4961–4972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fidler IJ . (1991). 7th Jan Waldenstrom Lecture. The biology of human cancer metastasis. Acta Oncol 30: 668–675.

    Article  CAS  PubMed  Google Scholar 

  • Gallagher ED, Gutowski S, Sternweis PC, Cobb MH . (2004). RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. J Biol Chem 279: 1872–1877.

    Article  CAS  PubMed  Google Scholar 

  • Gallo KA, Johnson GL . (2002). Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3: 663–672.

    Article  CAS  PubMed  Google Scholar 

  • Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC et al. (2004). Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306: 271–275.

    Article  CAS  PubMed  Google Scholar 

  • Garrington TP, Ishizuka T, Papst PJ, Chayama K, Webb S, Yujiri T et al. (2000). MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. EMBO J 19: 5387–5395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerwins P, Blank JL, Johnson GL . (1997). Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J Biol Chem 272: 8288–8295.

    Article  CAS  PubMed  Google Scholar 

  • Gollob JA, Wilhelm S, Carter C, Kelley SL . (2006). Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 33: 392–406.

    Article  CAS  PubMed  Google Scholar 

  • Gorgoulis VG, Zacharatos P, Mariatos G, Liloglou T, Kokotas S, Kastrinakis N et al. (2001). Deregulated expression of c-mos in non-small cell lung carcinomas: relationship with p53 status, genomic instability, and tumor kinetics. Cancer Res 61: 538–549.

    CAS  PubMed  Google Scholar 

  • Gotoh I, Adachi M, Nishida E . (2001). Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem 276: 4276–4286.

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa T, Matsuzawa A, Noguchi T, Takeda K, Ichijo H . (2006). The ASK1-MAP kinase pathways in immune and stress responses. Microbes Infect 8: 1098–1107.

    Article  CAS  PubMed  Google Scholar 

  • Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED, Eliceiri B et al. (2004). Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest 113: 1138–1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hollenbach E, Neumann M, Vieth M, Roessner A, Malfertheiner P, Naumann M . (2004). Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB J 18: 1550–1552.

    Article  CAS  PubMed  Google Scholar 

  • Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu ZG et al. (2004). Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol 5: 98–103.

    Article  CAS  PubMed  Google Scholar 

  • Hutchison M, Berman KS, Cobb MH . (1998). Isolation of TAO1, a protein kinase that activates MEKs in stress-activated protein kinase cascades. J Biol Chem 273: 28625–28632.

    Article  CAS  PubMed  Google Scholar 

  • Huttenlocher A, Palecek SP, Lu Q, Zhang W, Mellgren RL, Lauffenburger DA et al. (1997). Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem 272: 32719–32722.

    Article  CAS  PubMed  Google Scholar 

  • Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T et al. (1997). Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275: 90–94.

    Article  CAS  PubMed  Google Scholar 

  • Irie T, Muta T, Takeshige K . (2000). TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages. FEBS Lett 467: 160–164.

    Article  CAS  PubMed  Google Scholar 

  • Izumi Y, Kim S, Yoshiyama M, Izumiya Y, Yoshida K, Matsuzawa A et al. (2003). Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia. Circulation 108: 2812–2818.

    Article  CAS  PubMed  Google Scholar 

  • Jadrich JL, O’Connor MB, Coucouvanis E . (2006). The TGF beta activated kinase TAK1 regulates vascular development in vivo. Development 133: 1529–1541.

    Article  CAS  PubMed  Google Scholar 

  • Johnson GL, Dohlman HG, Graves LM . (2005). MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaling networks and gene expression. Curr Opin Chem Biol 9: 325–331.

    Article  CAS  PubMed  Google Scholar 

  • Johnson GL, Lapadat R . (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298: 1911–1912.

    Article  CAS  PubMed  Google Scholar 

  • Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A et al. (2004). TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell 15: 535–548.

    Article  CAS  PubMed  Google Scholar 

  • Karin M, Gallagher E . (2005). From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life 57: 283–295.

    Article  CAS  PubMed  Google Scholar 

  • Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD . (1997). BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J 16: 7054–7066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato Y, Zhao M, Morikawa A, Sugiyama T, Chakravortty D, Koide N et al. (2000). Big mitogen-activated kinase regulates multiple members of the MEF2 protein family. J Biol Chem 275: 18534–18540.

    Article  CAS  PubMed  Google Scholar 

  • Kesavan K, Lobel-Rice K, Sun W, Lapadat R, Webb S, Johnson GL et al. (2004). MEKK2 regulates the coordinate activation of ERK5 and JNK in response to FGF-2 in fibroblasts. J Cell Physiol 199: 140–148.

    Article  CAS  PubMed  Google Scholar 

  • Larkin JM, Eisen T . (2006). Kinase inhibitors in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol 60: 216–226.

    Article  PubMed  Google Scholar 

  • Lee JW, Soung YH, Kim SY, Park WS, Nam SW, Min WS et al. (2005). Mutational analysis of the ARAF gene in human cancers. APMIS 113: 54–57.

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Minamino T, Tsukamoto O, Yujiri T, Shintani Y, Okada K et al. (2005). Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model. Circulation 111: 1672–1678.

    Article  CAS  PubMed  Google Scholar 

  • Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T et al. (2003). Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73: 1459–1464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lund S, Porzgen P, Mortensen AL, Hasseldam H, Bozyczko-Coyne D, Morath S et al. (2005). Inhibition of microglial inflammation by the MLK inhibitor CEP-1347. J Neurochem 92: 1439–1451.

    Article  CAS  PubMed  Google Scholar 

  • Luo W, Ng WW, Jin LH, Ye Z, Han J, Lin SC . (2003). Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. J Biol Chem 278: 37451–37458.

    Article  CAS  PubMed  Google Scholar 

  • Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S et al. (2005). ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol 6: 587–592.

    Article  CAS  PubMed  Google Scholar 

  • Morrison DK, Davis RJ . (2003). Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol 19: 91–118.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura K, Johnson GL . (2003). PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J Biol Chem 278: 36989–36992.

    Article  CAS  PubMed  Google Scholar 

  • Nicol RL, Frey N, Pearson G, Cobb M, Richardson J, Olson EN . (2001). Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J 20: 2757–2767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T et al. (1995). Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. Cancer Res 55: 4182–4187.

    CAS  PubMed  Google Scholar 

  • Okazaki K, Sagata N . (1995). The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells. EMBO J 14: 5048–5059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Omori E, Matsumoto K, Sanjo H, Sato S, Akira S, Smart RC et al. (2006). TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem 281: 19610–19617.

    Article  CAS  PubMed  Google Scholar 

  • Parameswaran N, Pao CS, Leonhard KS, Kang DS, Kratz M, Ley SC et al. (2006). Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. J Biol Chem 281: 34159–34170.

    Article  CAS  PubMed  Google Scholar 

  • Patriotis C, Makris A, Bear SE, Tsichlis PN . (1993). Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. Proc Natl Acad Sci USA 90: 2251–2255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K et al. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22: 153–183.

    CAS  PubMed  Google Scholar 

  • Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL et al. (2006). Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24: 2505–2512.

    Article  CAS  PubMed  Google Scholar 

  • Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K . (2002). Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc Natl Acad Sci USA 99: 9248–9253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Regnier CH, Masson R, Kedinger V, Textoris J, Stoll I, Chenard MP et al. (2002). Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient mice. Proc Natl Acad Sci USA 99: 5585–5590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sagata N . (1997). What does Mos do in oocytes and somatic cells? Bioessays 19: 13–21.

    Article  CAS  PubMed  Google Scholar 

  • Sahoo T, Johnson EW, Thomas JW, Kuehl PM, Jones TL, Dokken CG et al. (1999). Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 8: 2325–2333.

    Article  CAS  PubMed  Google Scholar 

  • Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T et al. (2005). Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 6: 1087–1095.

    Article  CAS  PubMed  Google Scholar 

  • Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS et al. (2005). TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19: 2668–2681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohn SJ, Sarvis BK, Cado D, Winoto A . (2002). ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression. J Biol Chem 277: 43344–43351.

    Article  CAS  PubMed  Google Scholar 

  • Sourvinos G, Tsatsanis C, Spandidos DA . (1999). Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 18: 4968–4973.

    Article  CAS  PubMed  Google Scholar 

  • Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL et al. (2001). MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. J Biol Chem 276: 5093–5100.

    Article  CAS  PubMed  Google Scholar 

  • Sun W, Wei X, Kesavan K, Garrington TP, Fan R, Mei J et al. (2003). MEK kinase 2 and the adaptor protein Lad regulate extracellular signal-regulated kinase 5 activation by epidermal growth factor via Src. Mol Cell Biol 23: 2298–2308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB . (2003). TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol 326: 105–115.

    Article  CAS  PubMed  Google Scholar 

  • Takekawa M, Saito H . (1998). A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95: 521–530.

    Article  CAS  PubMed  Google Scholar 

  • Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K et al. (2001). ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2: 222–228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uhlik MT, Abell AN, Cuevas BD, Nakamura K, Johnson GL . (2004). Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. Biochem Cell Biol 82: 658–663.

    Article  CAS  PubMed  Google Scholar 

  • Uhlik MT, Abell AN, Johnson NL, Sun W, Cuevas BD, Lobel-Rice KE et al. (2003). Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 5: 1104–1110.

    Article  CAS  PubMed  Google Scholar 

  • Waldmeier P, Bozyczko-Coyne D, Williams M, Vaught JL . (2006). Recent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases. Biochem Pharmacol 72: 1197–1206.

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ . (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412: 346–351.

    Article  CAS  PubMed  Google Scholar 

  • Wei X, Sun W, Fan R, Hahn J, Joetham A, Li G et al. (2003). MEF2C regulates c-Jun but not TNF-alpha gene expression in stimulated mast cells. Eur J Immunol 33: 2903–2909.

    Article  CAS  PubMed  Google Scholar 

  • Wellbrock C, Karasarides M, Marais R . (2004). The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5: 875–885.

    Article  CAS  PubMed  Google Scholar 

  • Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ . (1995). Integration of MAP kinase signal transduction pathways at the serum response element. Science 269: 403–407.

    Article  CAS  PubMed  Google Scholar 

  • Willis AE . (1999). Translational control of growth factor and proto-oncogene expression. Int J Biochem Cell Biol 31: 73–86.

    Article  CAS  PubMed  Google Scholar 

  • Witowsky JA, Johnson GL . (2003). Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. J Biol Chem 278: 1403–1406.

    Article  CAS  PubMed  Google Scholar 

  • Wong CK, Luo W, Deng Y, Zou H, Ye Z, Lin SC . (2004). The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms. J Biol Chem 279: 39366–39373.

    Article  CAS  PubMed  Google Scholar 

  • Xia Y, Wang J, Xu S, Johnson GL, Hunter T, Lu Z . (2007). MEKK1 Mediates the Ubiquitination and Degradation of c-Jun in Response to Osmotic Stress. Mol Cell Biol 27: 510–517.

    Article  CAS  PubMed  Google Scholar 

  • Xu LG, Li LY, Shu HB . (2004). TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis. J Biol Chem 279: 17278–17282.

    Article  CAS  PubMed  Google Scholar 

  • Yamashita M, Ying SX, Zhang GM, Li C, Cheng SY, Deng CX et al. (2005). Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 121: 101–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur JS . (2003). Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol 3: 11.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang J, Boerm M, McCarty M, Bucana C, Fidler IJ, Zhuang Y et al. (2000). Mekk3 is essential for early embryonic cardiovascular development. Nat Genet 24: 309–313.

    Article  CAS  PubMed  Google Scholar 

  • Yew N, Strobel M, Vande Woude GF . (1993). Mos and the cell cycle: the molecular basis of the transformed phenotype. Curr Opin Genet Dev 3: 19–25.

    Article  CAS  PubMed  Google Scholar 

  • Yue J, Ferrell Jr JE . (2006). Mechanistic studies of the mitotic activation of Mos. Mol Cell Biol 26: 5300–5309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yujiri T, Sather S, Fanger GR, Johnson GL . (1998). Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science 282: 1911–1914.

    Article  CAS  PubMed  Google Scholar 

  • Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL et al. (2005). CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 14: 2521–2531.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Wang W, Hayashi Y, Jester JV, Birk DE, Gao M et al. (2003). A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure. EMBO J 22: 4443–4454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to B D Cuevas or G L Johnson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cuevas, B., Abell, A. & Johnson, G. Role of mitogen-activated protein kinase kinase kinases in signal integration. Oncogene 26, 3159–3171 (2007). https://doi.org/10.1038/sj.onc.1210409

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210409

Keywords

This article is cited by

Search

Quick links