mitogen activated protein kinase 6


Summary: A 97-kDa extracellular signal-regulated MAP kinase. Mitogen-activated protein kinase 6 levels increase during cellular differentiation, while in proliferating cells the enzyme is degraded rapidly via the PROTEASOME ENDOPEPTIDASE COMPLEX.

Top Publications

  1. Bhattacharjee B, Sengupta S. CpG methylation of HPV 16 LCR at E2 binding site proximal to P97 is associated with cervical cancer in presence of intact E2. Virology. 2006;354:280-5 pubmed
    ..These results indicate the involvement of E2 binding site methylation in presence of intact E2, leading to loss of E2 repressor activity in CaCx. ..
  2. Bogoyevitch M, Court N. Counting on mitogen-activated protein kinases--ERKs 3, 4, 5, 6, 7 and 8. Cell Signal. 2004;16:1345-54 pubmed
    ..It is clear from these studies that these additional ERKs show similarities to ERK1 and ERK2, but with some interesting differences that challenge the paradigm of the archetypical ERK1/2 MAPK pathway. ..
  3. Garcia Lora A, Martinez M, Pedrinaci S, Garrido F. Different regulation of PKC isoenzymes and MAPK by PSK and IL-2 in the proliferative and cytotoxic activities of the NKL human natural killer cell line. Cancer Immunol Immunother. 2003;52:59-64 pubmed
    ..IL-2 decreased the expression of ERK2, whereas PSK did not, and both agents increased the expression of ERK3. These results shown that PSK and IL-2 produce different variations in PKC isoenzymes and MAPK in NKL cells. ..
  4. Perander M, Keyse S, Seternes O. Does MK5 reconcile classical and atypical MAP kinases?. Front Biosci. 2008;13:4617-24 pubmed
    ..Thus, it is possible that MK5 is unique amongst the MAPKAP kinases in being regulated downstream of signaling pathways other than the classical MAP kinases p38 and ERK1/2. ..
  5. Coulombe P, Rodier G, Pelletier S, Pellerin J, Meloche S. Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation. Mol Cell Biol. 2003;23:4542-58 pubmed
    ..Interestingly, we found that expression of stabilized forms of ERK3 causes G(1) arrest in NIH 3T3 cells. We propose that ERK3 biological activity is regulated by its cellular abundance through the control of protein stability. ..
  6. Quarto N, Fong K, Longaker M. Gene profiling of cells expressing different FGF-2 forms. Gene. 2005;356:49-68 pubmed
    ..These results demonstrated that HMWFGF-2 and LMWFGF-2 target the expression of different genes. Particularly, our data suggest that HMWFGF-2 forms may function as inducers of growth inhibition and tumor suppression activities. ..
  7. Mikalsen T, Johannessen M, Moens U. Sequence- and position-dependent tagging protects extracellular-regulated kinase 3 protein from 26S proteasome-mediated degradation. Int J Biochem Cell Biol. 2005;37:2513-20 pubmed
    ..A stabilized variant may facilitate studies on the biological role of the protein. ..
  8. Limpert A, Karlo J, Landreth G. Nerve growth factor stimulates the concentration of TrkA within lipid rafts and extracellular signal-regulated kinase activation through c-Cbl-associated protein. Mol Cell Biol. 2007;27:5686-98 pubmed
    ..These data provide a mechanism for the lipid raft localization of TrkA and establish the importance of the CAP adaptor protein for NGF activation of the ERKs and neuronal differentiation. ..
  9. Coulombe P, Rodier G, Bonneil E, Thibault P, Meloche S. N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome. Mol Cell Biol. 2004;24:6140-50 pubmed
    ..Our results suggests that N-terminal ubiquitination is a more prevalent modification than originally recognized. ..

More Information


  1. Kim Y, Kim M, Im S, Kim T, Kim D, Yang H, et al. Metastasis-associated protein S100A4 and p53 predict relapse in curatively resected stage III and IV (M0) gastric cancer. Cancer Invest. 2008;26:152-8 pubmed publisher
    ..011) and 95% vs. 59% in stage IV (M0) (p = 0.003). In addition to staging system, the expressions of S100A4 and p53 were significant predictive factors of relapse in gastric cancer after curative resection and adjuvant chemotherapy. ..
  2. Almog T, Lazar S, Reiss N, Etkovitz N, Milch E, Rahamim N, et al. Identification of extracellular signal-regulated kinase 1/2 and p38 MAPK as regulators of human sperm motility and acrosome reaction and as predictors of poor spermatozoan quality. J Biol Chem. 2008;283:14479-89 pubmed publisher
    ..Therefore, increased expression of ERK1 and activated p38 can predict poor human sperm quality. ..
  3. Kashima H, Shiozawa T, Miyamoto T, Suzuki A, Uchikawa J, Kurai M, et al. Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E. Endocr Relat Cancer. 2009;16:113-22 pubmed publisher
    ..These findings suggest that E(2)-induced proliferation of endometrial carcinoma cells is mediated by the MAPK3/1 pathway via autocrine stimulation of IGF1. ..
  4. Beckers G, Jaskiewicz M, Liu Y, UNDERWOOD W, He S, Zhang S, et al. Mitogen-activated protein kinases 3 and 6 are required for full priming of stress responses in Arabidopsis thaliana. Plant Cell. 2009;21:944-53 pubmed publisher
    ..Our findings argue that prestress deposition of the signaling components MPK3 and MPK6 is a critical step in priming plants for full induction of defense responses during IR. ..
  5. Klinger S, Turgeon B, Lévesque K, Wood G, Aagaard Tillery K, Meloche S. Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality. Proc Natl Acad Sci U S A. 2009;106:16710-5 pubmed publisher
    ..Our findings reveal a critical role for Erk3 in the establishment of fetal growth potential and pulmonary function in the mouse. ..
  6. Meloche S, Beatty B, Pellerin J. Primary structure, expression and chromosomal locus of a human homolog of rat ERK3. Oncogene. 1996;13:1575-9 pubmed
    ..This information should prove valuable in designing studies to define the cellular function of the ERK3 protein kinase. ..
  7. Tanguay P, Rodier G, Meloche S. C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis. Biochem J. 2010;428:103-11 pubmed publisher
    ..The results of the present study identify a novel regulatory mechanism of ERK3 that operates in a cell-cycle-dependent manner. ..
  8. Zhu A, Zhao Y, Moller D, Flier J. Cloning and characterization of p97MAPK, a novel human homolog of rat ERK-3. Mol Cell Biol. 1994;14:8202-11 pubmed
    ..p97MAPK appears to be the human homolog of rat ERK-3, and a member of this family is an active protein kinase. ..
  9. Hoeflich K, Eby M, Forrest W, Gray D, Tien J, Stern H, et al. Regulation of ERK3/MAPK6 expression by BRAF. Int J Oncol. 2006;29:839-49 pubmed
    ..These results provide strong evidence for another mode by which BRAF can regulate the ERK protein kinase family and suggest ERK3 to be a potential pharmacodynamic marker for targeting BRAF signaling in melanoma. ..
  10. Liu H, Wang Y, Xu J, Su T, Liu G, Ren D. Ethylene signaling is required for the acceleration of cell death induced by the activation of AtMEK5 in Arabidopsis. Cell Res. 2008;18:422-32 pubmed publisher
    ..These data suggest that ethylene signaling perception is required to accelerate cell death that is induced by AtMEK5 activation. ..
  11. Bae G, Kim B, Lee H, Oh J, Lee S, Zhang W, et al. Cdo binds Abl to promote p38alpha/beta mitogen-activated protein kinase activity and myogenic differentiation. Mol Cell Biol. 2009;29:4130-43 pubmed publisher
    ..Abl's promyogenic effect is therefore linked to a multiprotein cell surface complex that regulates differentiation-dependent p38 activation. ..
  12. Maruyama Takahashi K, Shimada N, Imada T, Maekawa Tokuda Y, Ishii T, Ouchi J, et al. A neutralizing anti-fibroblast growth factor (FGF) 8 monoclonal antibody shows anti-tumor activity against FGF8b-expressing LNCaP xenografts in androgen-dependent and -independent conditions. Prostate. 2008;68:640-50 pubmed publisher
    ..Follow-up studies using xenograft models with clinical FGF8b-expressing tumors are required to validate these early findings. ..
  13. Bakker W, Sipkema P, Stehouwer C, Serne E, Smulders Y, van Hinsbergh V, et al. Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries. Diabetes. 2008;57:706-13 pubmed
    ..PKC theta activation induces insulin-mediated vasoconstriction by inhibition of Akt and stimulation of ERK1/2 in muscle resistance arteries. This provides a new mechanism linking PKC theta activation to insulin resistance. ..
  14. Liu H, Li W, Li X, Xu Q, Liu Q, Bai X, et al. Chitosan oligosaccharides inhibit the expression of interleukin-6 in lipopolysaccharide-induced human umbilical vein endothelial cells through p38 and ERK1/2 protein kinases. Basic Clin Pharmacol Toxicol. 2010;106:362-71 pubmed publisher
  15. Mizushima T, Obata K, Katsura H, Sakurai J, Kobayashi K, Yamanaka H, et al. Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity. J Pharmacol Exp Ther. 2007;321:28-34 pubmed
  16. Boulton T, Nye S, Robbins D, Ip N, Radziejewska E, Morgenbesser S, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65:663-75 pubmed
    ..Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals. ..
  17. Peng P, Chiou L, Chao H, Lin S, Chen C, Liu J, et al. Effects of epigallocatechin-3-gallate on rat retinal ganglion cells after optic nerve axotomy. Exp Eye Res. 2010;90:528-34 pubmed publisher
    ..Thus, we demonstrated that administration of EGCG prior to axotomy promotes RGC survival. The neuroprotective capacity of EGCG appears to act through mediating nitric oxide, anti-apoptotic, and cell survival signaling pathways. ..
  18. Sauma S, Friedman E. Increased expression of protein kinase C beta activates ERK3. J Biol Chem. 1996;271:11422-6 pubmed
    ..ERK3 activity was found in nuclear and membrane fractions in each PKC beta transfectant, in contrast to controls, perhaps accounting for constitutive activation of ERK3 in cells with elevated levels of PKC beta 1 or PKC beta 2. ..
  19. Turgeon B, Lang B, Meloche S. The protein kinase ERK3 is encoded by a single functional gene: genomic analysis of the ERK3 gene family. Genomics. 2002;80:673-80 pubmed
    ..Our analysis demonstrates that the ERK3 subfamily of MAP kinase genes is composed of two functional genes, MAPK6 and MAPK4, and several pseudogenes. ..
  20. Julien C, Coulombe P, Meloche S. Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression. J Biol Chem. 2003;278:42615-24 pubmed
    ..Our results suggest that nucleocytoplasmic shuttling of ERK3 is required for its negative regulatory effect on cell cycle progression. ..
  21. Crowe D. Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines. Int J Oncol. 2004;24:1159-63 pubmed
    ..These data represent the first reported function of p97MAPK in human cancer cells. ..
  22. Rai R, Mahale A, Saranath D. Molecular cloning, isolation and characterisation of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma. Oral Oncol. 2004;40:705-12 pubmed
    ..The overexpression of the gene in the normal healthy individuals may be indicative of increased risk of developing oral cancers in this group. ..
  23. Schumacher S, Laass K, Kant S, Shi Y, Visel A, Gruber A, et al. Scaffolding by ERK3 regulates MK5 in development. EMBO J. 2004;23:4770-9 pubmed
    ..Deletion of MK5 leads to strong reduction of ERK3 protein levels and embryonic lethality at about stage E11, where ERK3 expression in wild-type mice is maximum, indicating a role of this signalling module in development. ..
  24. Farinas I. Neurotrophin actions during the development of the peripheral nervous system. Microsc Res Tech. 1999;45:233-42 pubmed
    ..Many of these deficits occur before final target encounter. ..
  25. Shimada K, Nakamura M, Ishida E, Kishi M, Yonehara S, Konishi N. Contributions of mitogen-activated protein kinase and nuclear factor kappa B to N-(4-hydroxyphenyl)retinamide-induced apoptosis in prostate cancer cells. Mol Carcinog. 2002;35:127-37 pubmed
    ..It thus appears that mitogen-activated protein kinase associated with the activity of NFkappaB plays an important role in the degree of resistance to 4-HPR-induced apoptosis in human prostate cancer cells. ..
  26. Robinson M, Xu Be B, Stippec S, Cobb M. Different domains of the mitogen-activated protein kinases ERK3 and ERK2 direct subcellular localization and upstream specificity in vivo. J Biol Chem. 2002;277:5094-100 pubmed
  27. Ren D, Liu Y, Yang K, Han L, Mao G, Glazebrook J, et al. A fungal-responsive MAPK cascade regulates phytoalexin biosynthesis in Arabidopsis. Proc Natl Acad Sci U S A. 2008;105:5638-43 pubmed publisher
    ..These results indicate that the MPK3/MPK6 cascade regulates camalexin synthesis through transcriptional regulation of the biosynthetic genes after pathogen infection. ..
  28. Yao Z, Zhao B, Hoffman E, Ghimbovschi S, Dubois D, Almon R, et al. Application of scaling factors in simultaneous modeling of microarray data from diverse chips. Pharm Res. 2007;24:643-9 pubmed
    ..Modeling of pharmacodynamic/pharmacogenomic (PD/PG) data from diverse chips should be performed with caution due to differential probe set intensities. In such circumstances, a power scaling factor can be applied in the modeling. ..
  29. Ou J, Lowes C, Collinson J. Cytoskeletal and cell adhesion defects in wounded and Pax6+/- corneal epithelia. Invest Ophthalmol Vis Sci. 2010;51:1415-23 pubmed publisher
    ..These data show that cell junctions and cytoskeleton organization are dynamically remodeled in vivo by wounding and in Pax6(+/-) corneas. This apparent wound-healing phenotype contributes to the clinical aspects of ARK. ..
  30. Mandal A, Shahidullah M, Delamere N. Hydrostatic pressure-induced release of stored calcium in cultured rat optic nerve head astrocytes. Invest Ophthalmol Vis Sci. 2010;51:3129-38 pubmed publisher
    ..Increasing HP causes calcium release from a ryanodine-sensitive cytoplasmic store and subsequent ERK1/2 activation. Calcium store release appears to be a required early step in the initial astrocyte response to an HP increase. ..
  31. Müller J, Piffanelli P, Devoto A, Miklis M, Elliott C, Ortmann B, et al. Conserved ERAD-like quality control of a plant polytopic membrane protein. Plant Cell. 2005;17:149-63 pubmed
    ..This and a dependence on homologs of the AAA ATPase CDC48/p97 to eliminate the aberrant variants strongly suggest that MLO proteins are endogenous substrates of an ERAD-related plant quality control mechanism. ..
  32. Dingar D, Benoit M, Mamarbachi A, Villeneuve L, Gillis M, Grandy S, et al. Characterization of the expression and regulation of MK5 in the murine ventricular myocardium. Cell Signal. 2010;22:1063-75 pubmed publisher
    ..Hence, 1) in heart MK5 complexes with ERK3 and 2) MK5 splice variants may mediate distinct effects thus increasing the functional diversity of ERK3-MK5 signaling. ..
  33. Kling D, Brandon K, Sollinger C, Cavicchio A, Ge Q, Kinane T, et al. Distribution of ERK1/2 and ERK3 during normal rat fetal lung development. Anat Embryol (Berl). 2006;211:139-53 pubmed
    ..These observations will facilitate detailed functional analysis of these kinases to assess their roles in pulmonary development and diseases. ..
  34. Liang B, Wang S, Zhu X, Yu Y, Cui Z, Yu Y. Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. World J Gastroenterol. 2005;11:623-8 pubmed
    ..MEK-1 is also overexpressed in gastric cancer, particularly in metastatic lymph nodes. Upregulation of MAPK signal transduction pathways may play an important role in tumorigenesis and metastatic potential of gastric cancer. ..
  35. Sasseville M, Ritter L, Nguyen T, Liu F, Mottershead D, Russell D, et al. Growth differentiation factor 9 signaling requires ERK1/2 activity in mouse granulosa and cumulus cells. J Cell Sci. 2010;123:3166-76 pubmed publisher
  36. Turgeon B, Saba El Leil M, Meloche S. Cloning and characterization of mouse extracellular-signal-regulated protein kinase 3 as a unique gene product of 100 kDa. Biochem J. 2000;346 Pt 1:169-75 pubmed
    ..Finally, we provide several lines of evidence to support the existence of a unique Erk3 gene product of 100 kDa in mammalian cells. ..
  37. Aberg E, Torgersen K, Johansen B, Keyse S, Perander M, Seternes O. Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif. J Biol Chem. 2009;284:19392-401 pubmed publisher
  38. Adams V, Nehrhoff B, Späte U, Linke A, Schulze P, Baur A, et al. Induction of iNOS expression in skeletal muscle by IL-1beta and NFkappaB activation: an in vitro and in vivo study. Cardiovasc Res. 2002;54:95-104 pubmed
    ..These data demonstrate that IL-1beta, together with the priming effect of gamma-IFN, induces iNOS expression in skeletal muscle via activation of ERK1/ERK2 and NFkappaB. ..
  39. Hansen C, Bartek J, Jensen S. A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3. Cell Cycle. 2008;7:325-34 pubmed
    ..Collectively, our findings suggest an intimate functional relationship between the Cdc14A phosphatase and the Erk3 kinase in signaling pathways that regulate key cell-fate decisions in human cells. ..
  40. Bind E, Kleyner Y, Skowronska Krawczyk D, Bien E, Dynlacht B, SANCHEZ I. A novel mechanism for mitogen-activated protein kinase localization. Mol Biol Cell. 2004;15:4457-66 pubmed
    ..These data suggest a novel mechanism for the localization of an MAPK family member, ERK3, in which cell cycle-regulated, site-specific proteolysis generates the nuclear form of the protein. ..
  41. Seternes O, Mikalsen T, Johansen B, Michaelsen E, Armstrong C, Morrice N, et al. Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J. 2004;23:4780-91 pubmed
    ..Our findings provide valuable tools to further dissect the regulation and biological roles of both ERK3 and MK5. ..
  42. Kant S, Schumacher S, Singh M, Kispert A, Kotlyarov A, Gaestel M. Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5. J Biol Chem. 2006;281:35511-9 pubmed
    ..Interestingly, ERK4 dimerizes and/or oligomerizes with ERK3, suggesting that overexpressed inactive ERK3 recruits active endogenous ERK4 to MK5 for its activation. Hence, ERK3 and ERK4 cooperate in activation of MK5. ..
  43. Mizushima T, Obata K, Yamanaka H, Dai Y, Fukuoka T, Tokunaga A, et al. Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia. Pain. 2005;113:51-60 pubmed
  44. Anhê G, Torrão A, Nogueira T, Caperuto L, Amaral M, Medina M, et al. ERK3 associates with MAP2 and is involved in glucose-induced insulin secretion. Mol Cell Endocrinol. 2006;251:33-41 pubmed
    ..These observations provide evidence that ERK3 is involved in the regulation of stimulus-secretion coupling in pancreatic beta cells. ..
  45. Bai B, Tang J, Liu H, Chen J, Li Y, Song W. Apelin-13 induces ERK1/2 but not p38 MAPK activation through coupling of the human apelin receptor to the Gi2 pathway. Acta Biochim Biophys Sin (Shanghai). 2008;40:311-8 pubmed
    ..In conclusion, the ERK1/2, but not p38 MAPK pathway is activated by apelin-13 through coupling of human APJ to Gi2-protein, which contributes to cellular responses. ..
  46. Kim J, Kim J, Cho C, Jun H, Kim D, Yu Y, et al. Differential roles of matrix metalloproteinase-9 and -2, depending on proliferation or differentiation of retinoblastoma cells. Invest Ophthalmol Vis Sci. 2010;51:1783-8 pubmed publisher
    ..Therefore, therapeutic targeting to MMP-2 may prove useful for reducing malignancy through the differentiation of retinoblastoma cells. ..
  47. Hollborn M, Wiedemann P, Bringmann A, Kohen L. Chemotactic and cytotoxic effects of minocycline on human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2010;51:2721-9 pubmed publisher
    ..Low-dose minocycline induces the activation of RPE cells, as indicated by the activation of p38 and ERK1/2 and by enhanced chemotaxis mediated by autocrine PDGF signaling. High-dose minocycline induces RPE cell degeneration. ..
  48. Cheng M, Boulton T, Cobb M. ERK3 is a constitutively nuclear protein kinase. J Biol Chem. 1996;271:8951-8 pubmed
    ..Despite marked similarities to ERK1 and ERK2, ERK3 does not phosphorylate typical MAP kinase substrates, indicating that it has distinct functions. ..
  49. de Lemos L, Junyent F, Verdaguer E, Folch J, Romero R, Pallas M, et al. Differences in activation of ERK1/2 and p38 kinase in Jnk3 null mice following KA treatment. J Neurochem. 2010;114:1315-22 pubmed publisher
    ..Therefore, the data indicate that the lack of the JNK3 protein modulates other MAPKs and these changes could also have a pivotal role in neuroprotection. ..
  50. Lieberherr D, Thao N, Nakashima A, Umemura K, Kawasaki T, Shimamoto K. A sphingolipid elicitor-inducible mitogen-activated protein kinase is regulated by the small GTPase OsRac1 and heterotrimeric G-protein in rice 1[w]. Plant Physiol. 2005;138:1644-52 pubmed publisher
    ..These results indicate that these two G-proteins regulate an elicitor-inducible MAPK in rice at the protein level...
  51. Bethke G, Unthan T, Uhrig J, Pöschl Y, Gust A, Scheel D, et al. Flg22 regulates the release of an ethylene response factor substrate from MAP kinase 6 in Arabidopsis thaliana via ethylene signaling. Proc Natl Acad Sci U S A. 2009;106:8067-72 pubmed publisher
    ..ERF104 is a vital regulator of basal immunity, as altered expression in both erf104 and overexpressors led to more growth inhibition by flg22 and enhanced susceptibility to a non-adapted bacterial pathogen. ..
  52. Coulombe P, Meloche S. Dual-tag prokaryotic vectors for enhanced expression of full-length recombinant proteins. Anal Biochem. 2002;310:219-22 pubmed
  53. Jiang Y, Steinle J. Systemic propranolol reduces b-wave amplitude in the ERG and increases IGF-1 receptor phosphorylation in rat retina. Invest Ophthalmol Vis Sci. 2010;51:2730-5 pubmed publisher
    ..Systemic application of beta-adrenergic receptor antagonists may have detrimental effects on the retina. ..