Alternative titles; symbols
HGNC Approved Gene Symbol: MAPK3
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:30,114,105-30,123,220 (from NCBI)
Charest et al. (1993) cloned a cDNA encoding a member of a family of tyrosyl-phosphorylated and mitogen-activated protein kinases (MAPKs) that participates in cell cycle progression. They referred to the protein as p44(erk1) and the gene as ERK1. The cDNA encodes a 379-amino acid polypeptide sharing approximately 96% predicted amino acid identity with partial sequences of rodent erk1 cognates. They also characterized the enzyme biochemically.
Charest et al. (1993) mapped the MAPK3 gene to human chromosome 16 by hybrid cell panel analysis. Li et al. (1994) assigned human MAPK3 and MAPK1 to 16p11.2 and 22q11.2, respectively, by a combination of Southern blotting of a human-hamster hybrid panel and fluorescence in situ hybridization. The chromosome region surrounding 16p11.2 displays high homology with mouse chromosome 7, and human 22q11.2 is homologous to mouse chromosome 16. Saba-El-Leil et al. (1997) mapped the murine homolog (Mapk3) to mouse chromosome 7.
Experience-dependent plasticity in the developing visual cortex depends on electrical activity and molecular signals involved in stabilization or removal of inputs. ERK1 and ERK2 (MAPK1; 176948) activation in the cortex is regulated by both factors. Di Cristo et al. (2001) demonstrated that 2 different inhibitors of the ERK pathway suppress the induction of 2 forms of long-term potentiation in rat cortical slices and that their intracortical administration to monocularly deprived rats prevents the shift in ocular dominance towards the nondeprived eye. Di Cristo et al. (2001) concluded that the ERK pathway is necessary for experience-dependent plasticity and for long-term potentiation of synaptic transmission in the developing visual cortex.
Stefanovsky et al. (2001) showed that epidermal growth factor (131530) induces immediate, ERK1/ERK2-dependent activation of endogenous ribosomal transcription, while inactivation of ERK1/ERK2 causes an equally immediate reversion to the basal transcription level. ERK1/ERK2 was found to phosphorylate the architectural transcription factor UBF (600673) at amino acids 117 and 201 within HMG boxes 1 and 2, preventing their interaction with DNA. Mutation of these sites inhibited transcription activation and abrogated the transcriptional response to ERK1/ERK2. Thus, growth factor regulation of ribosomal transcription likely acts by a cyclic modulation of DNA architecture. The data suggested a central role for ribosome biogenesis in growth regulation.
Using an in situ phosphorylation screening strategy to identify protein kinase substrates, Fukunaga and Hunter (1997) identified MNK1 (MKNK1; 606724) as an ERK1 substrate. Using 2-hybrid tests and in vitro association experiments, Waskiewicz et al. (1997) demonstrated that mouse Mnk1 and Mnk2 (MKNK2; 605069) bind tightly to Erk1 and Erk2 through a C-terminal domain. Mnk1 complexes more strongly with inactive than active Erk, and the authors hypothesized that Mnk and Erk may dissociate after mitogen stimulation.
Forcet et al. (2002) showed that in embryonic kidney cells expressing full-length, but not cytoplasmic domain-truncated, DCC (120470), NTN1 (601614) causes increased transient phosphorylation and activity of ERK1 and ERK2, but not of JNK1 (601158), JNK2 (602896), or p38 (MAPK14; 600289). This phosphorylation was mediated by MEK1 (MAP2K1; 176872) and/or MEK2 (MAP2K2; 601263). NTN1 also activated the transcription factor ELK1 (311040) and serum response element-regulated gene expression. Immunoprecipitation analysis showed interaction of full-length DCC with MEK1/2 in the presence or absence of NTN1. Forcet et al. (2002) showed that activation of Dcc by Ntn1 in rat embryonic day-13 dorsal spinal cord stimulates and is required for the outgrowth of commissural axons and Erk1/2 activation. Immunohistochemical analysis demonstrated expression of activated Erk1/2 in embryonic commissural axons, and this expression was diminished in Dcc or Ntn1 knockout animals. Forcet et al. (2002) concluded that the MAPK pathway is involved in responses to NTN1 and proposed that ERK activation affects axonal growth by phosphorylation of microtubule-associated proteins and neurofilaments.
Anthrax lethal toxin (LT), a critical virulence factor of Bacillus anthracis, is a complex of lethal factor (LF) and protective antigen (PA). PA binds to the anthrax receptor (ATR; 606410) to facilitate the entry of LF into the cell. LT disrupts the MAPK signaling pathway in macrophages (Park et al., 2002). Agrawal et al. (2003) showed that, in mice, LT impairs the function of dendritic cells (DCs), inhibiting the upregulation of costimulatory molecules, such as CD40 (109535), CD80 (112203), and CD86 (601020), as well as cytokine secretion, in response to lipopolysaccharide stimulation. LT-exposed DCs failed to stimulate antigen-specific T and B cells in vivo, resulting in significant reductions of circulating IgG antibody. Western blot analysis indicated that LF severely impairs phosphorylation of p38, ERK1, and ERK2. A cocktail of synthetic MAPK inhibitors inhibited cytokine production in a manner similar to that of LF. Using a mutant form of LF lacking a catalytic site necessary for cleavage of MEK1, MEK2, and MEK3 (602314), the upstream activators of ERK1, ERK2, and p38, respectively, Agrawal et al. (2003) found that cleavage of these MEKs is essential for suppression of dendritic cell function. They proposed that this mechanism might operate early in infection, when LT levels are low, to impair immunity. Later in infection, Agrawal et al. (2003) noted, LT might have quite different inflammatory effects.
Imai et al. (2008) used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiologic compensation for insulin resistance. Imai et al. (2008) found that hepatic activation of ERK1 signaling by expression of constitutively active MEK1 (176872) induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, Imai et al. (2008) concluded that interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.
In mouse hearts with pressure-induced cardiac hypertrophy, Lorenz et al. (2009) observed strong phosphorylation of ERK1/ERK2 at thr183, and in failing human hearts, they found an approximately 5-fold increase in thr188 phosphorylation compared to controls. The authors demonstrated that thr188 autophosphorylation directs ERK1/ERK2 to phosphorylate nuclear targets known to cause cardiac hypertrophy, and that thr188 phosphorylation requires activation and assembly of the entire RAF (164760)-MEK-ERK kinase cascade, phosphorylation of the TEY motif, dimerization of ERK1/ERK2, and binding to G protein beta-gamma subunits (see 139390) released from activated Gq (see 600998). Experiments using transgenic mouse models carrying mutations at thr188 suggested a causal relationship to cardiac hypertrophy. Lorenz et al. (2009) proposed that specific phosphorylation events on ERK1/ERK2 integrate differing upstream signals to induce cardiac hypertrophy.
During early lung development, airway tubes change shape. Tube length increases more than circumference as a large proportion of lung epithelial cells divide parallel to the airway longitudinal axis. Tang et al. (2011) showed that this bias is lost in mutants with increased ERK1 and ERK2 activity, revealing a link between the ERK1/2 signaling pathway and the control of mitotic spindle orientation. Using a mathematical model, Tang et al. (2011) demonstrated that change in airway shape can occur as a function of spindle angle distribution determined by ERK1/2 signaling, independent of effects on cell proliferation or cell size and shape. Tang et al. (2011) identified sprouty genes (SPRY1, 602465; SPRY2, 602466), which encode negative regulators of fibroblast growth factor-10 (FGF10; 602115)-mediated RAS-regulated ERK1/2 signaling, as essential for controlling airway shape change during development through an effect on mitotic spindle orientation.
Chan et al. (2020) analyzed 1,148 patient-derived B-cell leukemia samples and found that individual mutations did not promote leukemogenesis unless they converged on a single oncogenic pathway characteristic of the differentiation stage of transformed B cells. Mutations that were not aligned with this central oncogenic driver activated divergent pathways and subverted transformation. Oncogenic lesions in B-ALL frequently mimicked signaling through cytokine receptors at the pro-B-cell stage, via activation of STAT5 (STAT5A; 601511), or pre-B-cell receptors in more mature cells, via activation of ERK. STAT5- and ERK-activating lesions were frequent but occurred together in only 3% of cases (P = 2.2 x 10-16). Single-cell mutation and phosphoprotein analyses revealed segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engaged opposing biochemical and transcriptional programs orchestrated by MYC (190080) and BCL6 (109565), respectively. Genetic reactivation of the divergent (i.e., suppressed) pathway came at the expense of the principal oncogenic driver and reversed transformation. Conversely, deletion of divergent pathway components accelerated leukemogenesis. Chan et al. (2020) concluded that persistence of divergent signaling pathways represents a powerful barrier to transformation, whereas convergence on 1 principal driver defines a central event in leukemia initiation. The findings showed that pharmacologic reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver, suggesting that reactivation of divergent pathways may provide a novel strategy to enhance treatment responses.
Pages et al. (1999) generated p44 Mapk (Erk1)-deficient mice by homologous recombination in embryonic stem cells. The p44 Mapk were viable, fertile, and of normal size. Thus, Pages et al. (1999) concluded that p44 Mapk is apparently dispensable and that p42 Mapk (Erk2) may compensate for its loss. However, in p44 Mapk -/- mice, thymocyte maturation beyond the CD4+CD8+ stage was reduced by half, with a similar diminution in the thymocyte subpopulation expressing high levels of T cell receptor (CD3-high). In p44 Mapk -/- thymocytes, proliferation in response to activation with a monoclonal antibody to the T cell receptor in the presence of phorbol myristate acetate was severely reduced even though activation of p42 Mapk was more sustained in these cells. Thus, Pages et al. (1999) concluded that p44 Mapk apparently has a specific role in thymocyte development.
In behavioral tests with mice lacking Erk1, Mazzucchelli et al. (2002) observed an enhancement of striatum-dependent long-term memory that correlated with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, ablation of Erk1 resulted in a stimulus-dependent increase of Erk2 signaling, which Mazzucchelli et al. (2002) stated was likely due to its enhanced interaction with the upstream kinase Mek. They concluded that Erk1 has a critical regulatory role in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.
A surge of luteinizing hormone (LH; see 152780) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS (190020) and ERK1/2 are activated by an LH surge in granulosa cells of preovulatory follicles, Fan et al. (2009) disrupted Erk1/2 in mouse granulosa cells and provided in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene (189965) in granulosa cells demonstrated that C/EBP-beta is a critical downstream mediator of ERK1/2 activation. Thus, Fan et al. (2009) concluded that ERK1/2 and C/EBP-beta constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.
Holm et al. (2011) showed that Erk1/2 and Smad2 (601366) are activated in a mouse model of Marfan syndrome, and both are inhibited by therapies directed against Tgf-beta (190180). Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 (600993) deficiency exacerbated aortic disease and caused premature death in Marfan syndrome mice. Smad4-deficient Marfan syndrome mice uniquely showed activation of Jnk1 (601158), and a Jnk antagonist ameliorated aortic growth in Marfan mice that lacked or retained full Smad4 expression. Thus, Holm et al. (2011) concluded that noncanonical (Smad-independent) Tgf-beta signaling is a prominent driver of aortic disease in Marfan syndrome mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.
Agrawal, A., Lingappa, J., Leppla, S. H., Agrawal, S., Jabbar, A., Quinn, C., Pulendran, B. Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 424: 329-334, 2003. [PubMed: 12867985] [Full Text: https://doi.org/10.1038/nature01794]
Chan, L. N., Murakami, M. A., Robinson, M. E., Caeser, R., Sadras, T., Lee, J., Cosgun, K. N., Kume, K., Khairnar, V., Xiao, G., Ahmed, M. A., Aghania, E., and 17 others. Signalling input from divergent pathways subverts B cell transformation. Nature 583: 845-851, 2020. [PubMed: 32699415] [Full Text: https://doi.org/10.1038/s41586-020-2513-4]
Charest, D. L., Mordret, G., Harder, K. W., Jirik, F., Pelech, S. L. Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1. Molec. Cell. Biol. 13: 4679-4690, 1993. [PubMed: 7687743] [Full Text: https://doi.org/10.1128/mcb.13.8.4679-4690.1993]
Di Cristo, G., Berardi, N., Cancedda, L., Pizzorusso, T., Putignano, E., Ratto, G. M., Maffei, L. Requirement of ERK activation for visual cortical plasticity. Science 292: 2337-2340, 2001. [PubMed: 11423664] [Full Text: https://doi.org/10.1126/science.1059075]
Fan, H.-Y., Liu, Z., Shimada, M., Sterneck, E., Johnson, P. F., Hedrick, S. M., Richards, J. S. MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science 324: 938-941, 2009. [PubMed: 19443782] [Full Text: https://doi.org/10.1126/science.1171396]
Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Nature 417: 443-447, 2002. [PubMed: 11986622] [Full Text: https://doi.org/10.1038/nature748]
Fukunaga, R., Hunter, T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 16: 1921-1933, 1997. [PubMed: 9155018] [Full Text: https://doi.org/10.1093/emboj/16.8.1921]
Holm, T. M., Habashi, J. P., Doyle, J. J., Bedja, D., Chen, Y., van Erp, C., Lindsay, M. E., Kim, D., Schoenhoff, F., Cohn, R. D., Loeys, B. L., Thomas, C. J., Patnaik, S., Marugan, J. J., Judge, D. P., Dietz, H. C. Noncanonical TGF-beta signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 332: 358-361, 2011. [PubMed: 21493862] [Full Text: https://doi.org/10.1126/science.1192149]
Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y. Regulation of pancreatic beta cell mass by neuronal signals from the liver. Science 322: 1250-1254, 2008. [PubMed: 19023081] [Full Text: https://doi.org/10.1126/science.1163971]
Li, L., Wysk, M., Gonzalez, F. A., Davis, R. J. Genomic loci of human mitogen-activated protein kinases. Oncogene 9: 647-649, 1994. [PubMed: 8290275]
Lorenz, K., Schmitt, J. P., Schmitteckert, E. M., Lohse, M. J. A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nature Med. 15: 75-83, 2009. [PubMed: 19060905] [Full Text: https://doi.org/10.1038/nm.1893]
Mazzucchelli, C., Vantaggiato, C., Ciamei, A., Fasano, S., Pakhotin, P., Krezel, W., Welzl, H., Wolfer, D. P., Pages, G., Valverde, O., Marowsky, A., Porrazzo, A., Orban, P. C., Maldonado, R., Ehrengruber, M. U., Cestari, V., Lipp, H.-P., Chapman, P. F., Pouyssegur, J., Brambilla, R. Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. Neuron 34: 807-820, 2002. [PubMed: 12062026] [Full Text: https://doi.org/10.1016/s0896-6273(02)00716-x]
Pages, G., Guerin, S., Grall, D., Bonino, F., Smith, A., Anjuere, F., Auberger, P., Pouyssegur, J. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286: 1374-1378, 1999. [PubMed: 10558995] [Full Text: https://doi.org/10.1126/science.286.5443.1374]
Park, J. M., Greten, F. R., Li, Z. W., Karin, M. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297: 2048-2051, 2002. [PubMed: 12202685] [Full Text: https://doi.org/10.1126/science.1073163]
Saba-El-Leil, M. K., Malo, D., Meloche, S. Chromosomal localization of the mouse genes encoding the ERK1 and ERK2 isoforms of MAP kinases. Mammalian Genome 8: 141-142, 1997. [PubMed: 9060415] [Full Text: https://doi.org/10.1007/s003359900374]
Stefanovsky, V. Y., Pelletier, G., Hannan, R., Gagnon-Kugler, T., Rothblum, L. I., Moss, T. An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Molec. Cell 8: 1063-1073, 2001. [PubMed: 11741541] [Full Text: https://doi.org/10.1016/s1097-2765(01)00384-7]
Tang, N., Marshall, W. F., McMahon, M., Metzger, R. J., Martin, G. R. Control of mitotic spindle angle by the RAS-regulated ERK1/2 pathway determines lung tube shape. Science 333: 342-345, 2011. [PubMed: 21764747] [Full Text: https://doi.org/10.1126/science.1204831]
Waskiewicz, A. J., Flynn, A., Proud, C. G., Cooper, J. A. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 16: 1909-1920, 1997. [PubMed: 9155017] [Full Text: https://doi.org/10.1093/emboj/16.8.1909]