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Gene Review

MAPK12  -  mitogen-activated protein kinase 12

Homo sapiens

Synonyms: ERK-6, ERK3, ERK6, Extracellular signal-regulated kinase 6, MAP kinase 12, ...
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Disease relevance of MAPK12

  • Inspection of the 17 genes uniquely regulated by ERK5 revealed that 14 genes (82%) were previously associated with hypoxia via regulation by HIF-1 [1].
  • These studies thus demonstrate the essential role of p38gamma in K-Ras transformation independent of phosphorylation, and elevated p38gamma may serve as a novel diagnostic marker and therapeutic target for human colon cancer [2].
  • The i.t. administration of ERK5 antisense oligodeoxynucleotide reversed heat hyperalgesia, but not mechanical allodynia, produced by capsaicin injection [3].
  • Taken together, these findings suggest that the in vivo activation of the ERK5 signaling pathway in sensory neurons by noxious stimulation may be, at least in part, correlated with functional activity and, further, involved in the development of pain hypersensitivity [3].
  • Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38gamma in human melanoma cells [4].

High impact information on MAPK12

  • Big MAP kinase (Bmk1), also known as Erk5, is a member of the MAP kinase family that is activated in cells in response to oxidative stress, hyperosmolarity and treatment with serum [5].
  • Interestingly, an NES mutant of c-Fos, but not wild-type, substitutes ERK5 activity for HeLa cell proliferation [6].
  • Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them [6].
  • ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32 [6].
  • Co-transfection with SAPKK3 induced SAPK3 activity and greatly enhanced activation in response to osmotic shock [7].

Biological context of MAPK12


Anatomical context of MAPK12


Associations of MAPK12 with chemical compounds


Physical interactions of MAPK12


Enzymatic interactions of MAPK12


Regulatory relationships of MAPK12


Other interactions of MAPK12


Analytical, diagnostic and therapeutic context of MAPK12


  1. Global gene expression analysis of ERK5 and ERK1/2 signaling reveals a role for HIF-1 in ERK5-mediated responses. Schweppe, R.E., Cheung, T.H., Ahn, N.G. J. Biol. Chem. (2006) [Pubmed]
  2. Essential role of p38gamma in K-Ras transformation independent of phosphorylation. Tang, J., Qi, X., Mercola, D., Han, J., Chen, G. J. Biol. Chem. (2005) [Pubmed]
  3. Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity. Mizushima, T., Obata, K., Katsura, H., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T., Mashimo, T., Noguchi, K. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  4. Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38gamma in human melanoma cells. Pillaire, M.J., Nebreda, A.R., Darbon, J.M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  5. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Kato, Y., Tapping, R.I., Huang, S., Watson, M.H., Ulevitch, R.J., Lee, J.D. Nature (1998) [Pubmed]
  6. Spatiotemporal Regulation of c-Fos by ERK5 and the E3 Ubiquitin Ligase UBR1, and Its Biological Role. Sasaki, T., Kojima, H., Kishimoto, R., Ikeda, A., Kunimoto, H., Nakajima, K. Mol. Cell (2006) [Pubmed]
  7. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). Cuenda, A., Cohen, P., Buée-Scherrer, V., Goedert, M. EMBO J. (1997) [Pubmed]
  8. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Wang, X., McGowan, C.H., Zhao, M., He, L., Downey, J.S., Fearns, C., Wang, Y., Huang, S., Han, J. Mol. Cell. Biol. (2000) [Pubmed]
  9. The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. Tosti, E., Waldbaum, L., Warshaw, G., Gross, E.A., Ruggieri, R. J. Biol. Chem. (2004) [Pubmed]
  10. Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor. Ambrose, M., Ryan, A., O'Sullivan, G.C., Dunne, C., Barry, O.P. Mol. Pharmacol. (2006) [Pubmed]
  11. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. Goedert, M., Hasegawa, M., Jakes, R., Lawler, S., Cuenda, A., Cohen, P. FEBS Lett. (1997) [Pubmed]
  12. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Lechner, C., Zahalka, M.A., Giot, J.F., Møller, N.P., Ullrich, A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  13. p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle. Ho, R.C., Alcazar, O., Fujii, N., Hirshman, M.F., Goodyear, L.J. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  14. Structure of GSK3beta reveals a primed phosphorylation mechanism. ter Haar, E., Coll, J.T., Austen, D.A., Hsiao, H.M., Swenson, L., Jain, J. Nat. Struct. Biol. (2001) [Pubmed]
  15. Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition. Hasegawa, M., Cuenda, A., Spillantini, M.G., Thomas, G.M., Buée-Scherrer, V., Cohen, P., Goedert, M. J. Biol. Chem. (1999) [Pubmed]
  16. Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. Alonso, G., Ambrosino, C., Jones, M., Nebreda, A.R. J. Biol. Chem. (2000) [Pubmed]
  17. Contributions of the mitogen-activated protein (MAP) kinase backbone and phosphorylation loop to MEK specificity. Robinson, M.J., Cheng, M., Khokhlatchev, A., Ebert, D., Ahn, N., Guan, K.L., Stein, B., Goldsmith, E., Cobb, M.H. J. Biol. Chem. (1996) [Pubmed]
  18. p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Qi, X., Tang, J., Loesch, M., Pohl, N., Alkan, S., Chen, G. Cancer Res. (2006) [Pubmed]
  19. Inhibition of TRAIL-induced apoptosis by IL-8 is mediated by the p38-MAPK pathway in OVCAR3 cells. Abdollahi, T., Robertson, N.M., Abdollahi, A., Litwack, G. Apoptosis (2005) [Pubmed]
  20. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. Chao, T.H., Hayashi, M., Tapping, R.I., Kato, Y., Lee, J.D. J. Biol. Chem. (1999) [Pubmed]
  21. Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization. Goedert, M., Hasegawa, J., Craxton, M., Leversha, M.A., Clegg, S. Genomics (1997) [Pubmed]
  22. Phosphorylation of cytosolic phospholipase A2 in platelets is mediated by multiple stress-activated protein kinase pathways. Börsch-Haubold, A.G., Ghomashchi, F., Pasquet, S., Goedert, M., Cohen, P., Gelb, M.H., Watson, S.P. Eur. J. Biochem. (1999) [Pubmed]
  23. Preconditioning-induced activation of ERK5 is dependent on moderate Ca(2+) influx via NMDA receptors and contributes to ischemic tolerance in the hippocampal CA1 region of rats. Wang, R.M., Yang, F., Zhang, Y.X. Life Sci. (2006) [Pubmed]
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