map kinase kinase 6


Summary: A mitogen-activated protein kinase kinase with specificity for P38 MITOGEN-ACTIVATED PROTEIN KINASES.

Top Publications

  1. Han J, Lee J, Jiang Y, Li Z, Feng L, Ulevitch R. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996;271:2886-91 pubmed
    ..This suggests novel mechanisms regulating activation and/or function of various forms of MKK6. ..
  2. Kelkar N, Standen C, Davis R. Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Mol Cell Biol. 2005;25:2733-43 pubmed
    ..The JIP4 scaffold protein therefore appears to be a new component of the p38 MAP kinase signaling pathway. ..
  3. Mikami F, Gu H, Jono H, Andalibi A, Kai H, Li J. Epidermal growth factor receptor acts as a negative regulator for bacterium nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling pathway. J Biol Chem. 2005;280:36185-94 pubmed
    ..These studies may bring new insight for fully understanding the important role of EGFR signaling in regulating host defense and immune response by tightly controlling TLR2 induction during bacterial infections. ..
  4. Kaur R, Liu X, Gjoerup O, Zhang A, Yuan X, Balk S, et al. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005;280:3323-30 pubmed
    ..mitogen-activated protein (MAP) kinase antagonist and could be strongly stimulated by constitutively active MAP kinase kinase 6 (MKK6), an upstream activator of p38 MAP kinases...
  5. Wall J, Wei J, Ly M, Belmont P, Martindale J, Tran D, et al. Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6. Am J Physiol Heart Circ Physiol. 2006;291:H2462-72 pubmed
  6. Jörgl A, Platzer B, Taschner S, Heinz L, Höcher B, Reisner P, et al. Human Langerhans-cell activation triggered in vitro by conditionally expressed MKK6 is counterregulated by the downstream effector RelB. Blood. 2007;109:185-93 pubmed
    ..a.MKK6-induced LC activation further enhanced their maturation state. This observation was validated using the p38 activator anisomycin, thus suggesting a novel LC intrinsic control mechanism regulated by RelB. ..
  7. Hernandez Losa J, Parada Cobo C, Guinea Viniegra J, Sánchez Arévalo Lobo V, Ramon Y Cajal S, Sanchez Prieto R. Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene. 2003;22:3998-4006 pubmed
    ..Therefore, we conclude that the p38 MAPK pathway is a specific target for cisplatin-based therapy with clinical implications. ..
  8. Degousee N, Martindale J, Stefanski E, Cieslak M, Lindsay T, Fish J, et al. MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. Circ Res. 2003;92:757-64 pubmed
    ..The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in ..
  9. Ambrosino C, Mace G, Galban S, Fritsch C, Vintersten K, Black E, et al. Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase. Mol Cell Biol. 2003;23:370-81 pubmed
    ..Our data indicate that p38alpha can negatively regulate the stability of the MKK6 mRNA and thus control the steady-state concentration of one of its upstream activators. ..

More Information


  1. Takenaka K, Moriguchi T, Nishida E. Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science. 1998;280:599-602 pubmed
    ..Treatment of NIH 3T3 cells with a specific inhibitor of p38 suppressed activation of the checkpoint by nocodazole. Thus, p38 functions as a component of the spindle assembly checkpoint in somatic cell cycles. ..
  2. Wang X, McGowan C, Zhao M, He L, Downey J, Fearns C, et al. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000;20:4543-52 pubmed
  3. Takekawa M, Posas F, Saito H. A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J. 1997;16:4973-82 pubmed
    ..These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway, and is also a minor mediator of the JNK pathway. ..
  4. Hsieh C, Papaconstantinou J. The effect of aging on p38 signaling pathway activity in the mouse liver and in response to ROS generated by 3-nitropropionic acid. Mech Ageing Dev. 2002;123:1423-35 pubmed
  5. Sorci G, Riuzzi F, Arcuri C, Giambanco I, Donato R. Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol. 2004;24:4880-94 pubmed
    ..These data suggest that RAGE and amphoterin might play an important role in myogenesis, accelerating myogenic differentiation via Cdc42-Rac-1-MAPK kinase 6-p38 MAPK. ..
  6. Watanabe T, Jono H, Han J, Lim D, Li J. Synergistic activation of NF-kappaB by nontypeable Haemophilus influenzae and tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 2004;101:3563-8 pubmed
    ..These studies should deepen our understanding of the molecular mechanisms underlying the combinatorial regulation of inflammation and lead to development of therapeutic strategies for NTHi-induced infections. ..
  7. Ben Levy R, Hooper S, Wilson R, Paterson H, Marshall C. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol. 1998;8:1049-57 pubmed
    ..Nuclear export of p38 and MAPKAP kinase-2 may permit them to phosphorylate substrates in the cytoplasm. ..
  8. Efimova T, Broome A, Eckert R. Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signal-regulated kinase 1/2 complex. Mol Cell Biol. 2004;24:8167-83 pubmed
    ..This regulation appears to be physiological, since H(2)O(2), a known inducer of keratinocyte apoptosis, promotes identical PKCdelta and p38delta-ERK1/2 activity changes, leading to similar morphological changes. ..
  9. Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch R, et al. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science. 2002;295:1291-4 pubmed
    ..These findings suggest that alternative activation pathways contribute to the biological responses of p38alpha to various stimuli. ..
  10. Moriguchi T, Toyoshima F, Gotoh Y, Iwamatsu A, Irie K, Mori E, et al. Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2. J Biol Chem. 1996;271:26981-8 pubmed
    ..Thus, there are at least three members of p38 activator, MKK3, MKK3b, and MAPKK6, and MAPKK6 may function as a major activator for p38 when expressed. ..
  11. Remy G, Risco A, Iñesta Vaquera F, González Terán B, Sabio G, Davis R, et al. Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal. 2010;22:660-7 pubmed publisher
    ..These data indicate that activation of distinct p38MAPK isoforms is regulated by the selective and synchronized action of two kinases, MKK3 and MKK6, in response to cell stress. ..
  12. Adhikary G, Chew Y, Reece E, Eckert R. PKC-delta and -eta, MEKK-1, MEK-6, MEK-3, and p38-delta are essential mediators of the response of normal human epidermal keratinocytes to differentiating agents. J Invest Dermatol. 2010;130:2017-30 pubmed publisher
    ..These findings are informative as they suggest an essential role for selected PKC and MAPK cascade enzymes in mediating a range of end responses to a range of differentiation stimuli in keratinocytes. ..
  13. Arning L, Monte D, Hansen W, Wieczorek S, Jagiello P, Akkad D, et al. ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. J Mol Med (Berl). 2008;86:485-90 pubmed publisher
  14. Miska E, Langley E, Wolf D, Karlsson C, Pines J, Kouzarides T. Differential localization of HDAC4 orchestrates muscle differentiation. Nucleic Acids Res. 2001;29:3439-47 pubmed
    ..However, despite the functional similarities of HDAC4 and HDAC5, their intracellular localisations are opposed, suggesting a distinct role for these enzymes during muscle differentiation. ..
  15. Bodart J, Chopra A, Liang X, Duesbery N. Anthrax, MEK and cancer. Cell Cycle. 2002;1:10-5 pubmed
  16. Otto K, Acharya S, Robinson V. Stress-activated kinase pathway alteration is a frequent event in bladder cancer. Urol Oncol. 2012;30:415-20 pubmed publisher
    ..Further investigations should focus on identifying a functional role for these pathways in bladder cancer development. ..
  17. Shuto T, Xu H, Wang B, Han J, Kai H, Gu X, et al. Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl Acad Sci U S A. 2001;98:8774-9 pubmed
    ..These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases. ..
  18. Ohira T, Bannenberg G, Arita M, Takahashi M, Ge Q, Van Dyke T, et al. A stable aspirin-triggered lipoxin A4 analog blocks phosphorylation of leukocyte-specific protein 1 in human neutrophils. J Immunol. 2004;173:2091-8 pubmed
  19. Marinissen M, Chiariello M, Gutkind J. Regulation of gene expression by the small GTPase Rho through the ERK6 (p38 gamma) MAP kinase pathway. Genes Dev. 2001;15:535-53 pubmed
    ..Furthermore, we present evidence that RhoA, PKN, MKK3/MKK6, and ERK6 (p38 gamma) are components of a novel signal transduction pathway involved in the regulation of gene expression and cellular transformation. ..
  20. Chang A. Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death. J Biomed Sci. 2012;19:96 pubmed publisher
  21. Zheng L, Zhang Y, Wu J, Wu Z, Zhang Z, Wang Z. A continuous spectrophotometric assay for mitogen-activated protein kinase kinases. Anal Biochem. 2012;421:191-7 pubmed publisher
    ..Our findings of the MAPK kinases in the current study provide evidence that the substrate binding affinities of this subfamily of protein kinases are at the submicromolar concentration. ..
  22. Kang S, Jung M, Kim C, Shin D. Inactivation of p38 kinase delays the onset of senescence in rabbit articular chondrocytes. Mech Ageing Dev. 2005;126:591-7 pubmed
  23. Fukuda R, Suico M, Koyama K, Omachi K, Kai Y, Matsuyama S, et al. Mild electrical stimulation at 0.1-ms pulse width induces p53 protein phosphorylation and G2 arrest in human epithelial cells. J Biol Chem. 2013;288:16117-26 pubmed publisher
    ..These findings identify some molecular targets of electrical stimulation and incorporate the p38-p53 signaling pathway among the transduction pathways that MES affects. ..
  24. Vahebi S, Ota A, Li M, Warren C, de Tombe P, Wang Y, et al. p38-MAPK induced dephosphorylation of alpha-tropomyosin is associated with depression of myocardial sarcomeric tension and ATPase activity. Circ Res. 2007;100:408-15 pubmed
    ..These data are the first to indicate that chronic activation of p38alpha MAPK directly depresses sarcomeric function in association with decreased phosphorylation of alpha-tropomyosin. ..
  25. Gills J, Castillo S, Zhang C, Petukhov P, Memmott R, Hollingshead M, et al. Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J Biol Chem. 2007;282:27020-9 pubmed
    ..Independent modulation of Akt and p38alpha could account for the profound cytotoxicity of PIAs. ..
  26. Song J, Li J, Qiao J, Jain S, Mark Evers B, Chung D. PKD prevents H2O2-induced apoptosis via NF-kappaB and p38 MAPK in RIE-1 cells. Biochem Biophys Res Commun. 2009;378:610-4 pubmed publisher
    ..Our findings suggest that PKD protects intestinal cells through up-regulation of NF-kappaB and down-regulation of p38 MAPK. ..
  27. Ding N, Xiao H, Xu L, She S. [Effect of mitogen-activated protein kinase kinase 6-p38 alpha signal pathway on receptor for advanced glycation end-product expression in alveolar epithelial cells induced by mechanical stretch]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2009;21:597-600 pubmed
    ..MKK6 p38 alpha signaling pathway regulates the expression of RAGE induced by mechanical stretch in A549 cells. ..
  28. Keren A, Bengal E. Studying MAP Kinase pathways during early development of Xenopus laevis. Methods Mol Biol. 2010;661:409-20 pubmed publisher
    ..Finally, we describe an in vitro kinase assay specifically designed for the Xenopus embryo. ..
  29. Kosetsu K, Matsunaga S, Nakagami H, Colcombet J, Sasabe M, Soyano T, et al. The MAP kinase MPK4 is required for cytokinesis in Arabidopsis thaliana. Plant Cell. 2010;22:3778-90 pubmed publisher
    ..These results indicate that MPK4 is the downstream target of MKK6/ANQ in the regulation of cytokinesis in Arabidopsis and that MPK11 is also involved in cytokinesis. ..
  30. Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, et al. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996;271:13675-9 pubmed
    ..In addition, co-expression of TAK1 and p38/MPK2 in cells resulted in activation of p38/MPK2. These results indicate the existence of a novel kinase cascade consisting of TAK1, MAPKK6/MKK3, and p38/MPK2. ..
  31. Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, et al. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem. 1997;272:30122-8 pubmed
    ..Nonetheless important differences exist among the four members of the p38 group of enzymes, and thus each may have highly specific, individual contributions to biologic events involving activation of the p38 pathways. ..
  32. Johnson R, Huong S, Huang E. Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38. J Virol. 2000;74:1158-67 pubmed
    ..These findings indicate that HCMV has developed multiple mechanisms to ensure activation of the MAPK p38, a kinase critical to viral infection. ..
  33. Braz J, Bueno O, Liang Q, Wilkins B, Dai Y, Parsons S, et al. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J Clin Invest. 2003;111:1475-86 pubmed
    ..Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling. ..
  34. So H, Rho J, Jeong D, Park R, Fisher D, Ostrowski M, et al. Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem. 2003;278:24209-16 pubmed
    ..1 and MITF transcription factors synergistically activate OSCAR gene expression. Moreover, the activation of OSCAR gene expression by PU.1/MITF is further enhanced by the TRANCE-induced MKK6/p38 signaling cascade. ..
  35. Akimoto T, Pohnert S, Li P, Zhang M, Gumbs C, Rosenberg P, et al. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem. 2005;280:19587-93 pubmed
    ..These findings suggest that contractile activity-induced activation of the p38 MAPK pathway promotes Pgc-1alpha gene expression and skeletal muscle adaptation. ..
  36. Kumagai T, Nakamura Y, Osawa T, Uchida K. Role of p38 mitogen-activated protein kinase in the 4-hydroxy-2-nonenal-induced cyclooxygenase-2 expression. Arch Biochem Biophys. 2002;397:240-5 pubmed
    ..Furthermore, we also found that HNE upregulated the COX-2 expression by the stabilization of COX-2 mRNA via the p38 MAPK pathway. ..
  37. Terada Y, Nakashima O, Inoshita S, Kuwahara M, Sasaki S, Marumo F. TGF-beta-activating kinase-1 inhibits cell cycle and expression of cyclin D1 and A in LLC-PK1 cells. Kidney Int. 1999;56:1378-90 pubmed
    ..Cyclin D1 and A promoter activity and cell cycle progression in renal tubular cells are negatively regulated by the TAK1-MKK6-p38K pathway and positively regulated by the MKK1-p42/44MAPK pathway. ..
  38. Galanis A, Yang S, Sharrocks A. Selective targeting of MAPKs to the ETS domain transcription factor SAP-1. J Biol Chem. 2001;276:965-73 pubmed
    ..Our data therefore demonstrate that a modular system of motifs is responsible for directing specific MAPK subtypes to SAP-1, but also point to important distinctions in the mechanism of action of the D-domain and FXF motif. ..
  39. Rane M, Coxon P, Powell D, Webster R, Klein J, Pierce W, et al. p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils. J Biol Chem. 2001;276:3517-23 pubmed
    ..We conclude that Akt exists in a signaling complex containing p38 kinase, MK2, and Hsp27 and that p38-dependent MK2 activation functions as PDK2 in human neutrophils. ..
  40. Sawada Y, Nakamura K, Doi K, Takeda K, Tobiume K, Saitoh M, et al. Rap1 is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase. J Cell Sci. 2001;114:1221-7 pubmed
    ..Thus, Rap1 plays a unique role in force-initiated signal transduction. ..
  41. Huang H, Li Y, Chung M. Activin A induction of erythroid differentiation through MKK6-p38alpha/p38beta pathway is inhibited by follistatin. J Cell Physiol. 2010;223:687-94 pubmed publisher
    ..These results demonstrate that activin A induces erythroid differentiation of K562 cells through activation of MKK6-p38alpha/p38beta pathway and follistatin inhibits those effects. ..
  42. Yen A, Yang J. Cdc20 proteolysis requires p38 MAPK signaling and Cdh1-independent APC/C ubiquitination during spindle assembly checkpoint activation by cadmium. J Cell Physiol. 2010;223:327-34 pubmed publisher
    ..In summary, accelerated ubiquitination and proteolysis of Cdc20 is essential for prometaphase arrest that is mediated via the p38 signaling during SAC activation. ..
  43. Maizels E, Mukherjee A, Sithanandam G, Peters C, Cottom J, Mayo K, et al. Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. Mol Endocrinol. 2001;15:716-33 pubmed
    ..Thus MAPKAPK-3 is indeed uniquely poised to support luteal maturation through the phosphorylation and activation of the nuclear transcription factor CREB. ..
  44. Mita H, Tsutsui J, Takekawa M, Witten E, Saito H. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol Cell Biol. 2002;22:4544-55 pubmed
    ..These MTK1 mutants are constitutively active, in both yeast and mammalian cells. A model of MTK1 autoinhibition by the N-terminal inhibitory domain and activation by GADD45 binding is presented. ..
  45. Prickett T, Ninomiya Tsuji J, Broglie P, Muratore Schroeder T, Shabanowitz J, Hunt D, et al. TAB4 stimulates TAK1-TAB1 phosphorylation and binds polyubiquitin to direct signaling to NF-kappaB. J Biol Chem. 2008;283:19245-54 pubmed publisher
    ..The results show that TAB4 binds TAK1 and polyubiquitin chains to promote specific sites of phosphorylation in TAK1-TAB1, which activates IKK signaling to NF-kappaB. ..
  46. Iyoda K, Sasaki Y, Horimoto M, Toyama T, Yakushijin T, Sakakibara M, et al. Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer. 2003;97:3017-26 pubmed
    ..05). These findings suggested that reduction of the p38 MAPK cascade may account, in part, for the resistance to apoptosis, leading to the unrestricted cell growth of human HCC. ..
  47. Huang C, You J, Wu M, Hsu K. Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004;279:12286-92 pubmed
    ..These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors. ..
  48. Suelves M, Lluis F, Ruiz V, Nebreda A, Munoz Canoves P. Phosphorylation of MRF4 transactivation domain by p38 mediates repression of specific myogenic genes. EMBO J. 2004;23:365-75 pubmed
    ..We propose that repression of MRF4 activity by p38 phosphorylation may represent a new mechanism for the silencing of specific muscle genes at the terminal stages of muscle differentiation. ..
  49. Jomary C, Cullen J, Jones S. Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse. Invest Ophthalmol Vis Sci. 2006;47:1620-9 pubmed
  50. Kocer S, Walker S, Zerler B, Golub L, Simon S. Metalloproteinase inhibitors, nonantimicrobial chemically modified tetracyclines, and ilomastat block Bacillus anthracis lethal factor activity in viable cells. Infect Immun. 2005;73:7548-57 pubmed
    ..These results offer promise for strategies to combat effects of the lethal toxin of B. anthracis. ..
  51. Szafranska A, Luo X, Dalby K. Following in vitro activation of mitogen-activated protein kinases by mass spectrometry and tryptic peptide analysis: purifying fully activated p38 mitogen-activated protein kinase alpha. Anal Biochem. 2005;336:1-10 pubmed
    ..This approach offers the only means to specifically determine both stoichiometry and specificity of p38 MAPKalpha phosphorylation. ..
  52. Hsieh C, Kuro O M, Rosenblatt K, Brobey R, Papaconstantinou J. The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging. Aging (Albany NY). 2010;2:597-611 pubmed
    ..activating ASK1-signalosomes. We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center. ..
  53. Mukherjee S, Keitany G, Li Y, Wang Y, Ball H, Goldsmith E, et al. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science. 2006;312:1211-4 pubmed
    ..The acetylation on MAPKK6 directly competed with phosphorylation, preventing activation of the modified protein. This covalent modification may be used as a general regulatory mechanism in biological signaling. ..