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MAPK1 (mitogen-activated protein kinase 1)

Written2010-01Seda Tuncay, Sreeparna Banerjee
Department of Biological Sciences, Middle East Technical University, Ankara 06531, Turkey

(Note : for Links provided by Atlas : click)


Other aliasEC
LocusID (NCBI) 5594
Atlas_Id 41288
Location 22q11.21  [Link to chromosome band 22q11]
Location_base_pair Starts at and ends at bp from pter
Local_order According to NCBI Map Viewer, genes flanking ERK2 (MAPK1) in centromere to telomere direction on 22q11.2; 22q11.21 are:
- PPIL2, peptidylprolyl isomerase (cyclophilin)-like 2, Location: 22q11.21
- YPEL1, yippee-like 1 (Drosophila), Location: 22q11.2
- MAPK1, 22q11.22
- PPM1F, protein phosphatase 1F (PP2C domain containing), Location: 22q11.22
- LOC100286925, hypothetical protein LOC100286925, Location: 22q11.22
- LOC100286894, hypothetical protein LOC100286894, Location: 22q11.22
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CRKL (22q11.21) / MAPK1 (22q11.21)CRKL (22q11.21) / MAPK1 (22q11.22)HIVEP1 (6p24.1) / MAPK1 (22q11.21)
HIVEP1 (6p24.1) / MAPK1 (22q11.22)MAPK1 (22q11.21) / ARHGEF7 (13q34)MAPK1 (22q11.21) / ATP1A1 (1p13.1)
MAPK1 (22q11.21) / CASP1 (11q22.3)MAPK1 (22q11.21) / CLIP2 (7q11.23)MAPK1 (22q11.21) / EEF1AKMT3 (12q14.1)
MAPK1 (22q11.21) / GPR107 (9q34.11)MAPK1 (22q11.21) / KCNJ4 (22q13.1)MAPK1 (22q11.21) / MAPK1 (22q11.21)
MAPK1 (22q11.21) / PACS1 (11q13.1)MAPK1 (22q11.21) / RFT1 (3p21.1)MAPK1 (22q11.21) / TOP3B (22q11.22)
MAPK1 (22q11.21) / ZNF638 (2p13.2)MAPK1 (22q11.22) / ARHGEF7 (13q34)MAPK1 (22q11.22) / EEF1AKMT3 (12q14.1)
MAPK1 (22q11.22) / KCNJ4 (22q13.1)MAPK1 (22q11.22) / TOP3B (22q11.22)SERPINB5 (18q21.33) / MAPK1 (22q11.21)


  Diagram of the ERK2 (MAPK1) gene (isoform 1). Exons are represented by open boxes (in scale). Exons 1 to 8 are from the 5' to 3' direction.
Description According to Entrez Gene ERK2 (MAPK1) gene maps to NC_000022.10 and spans a region of 98.64 kb. According to Spidey mRNA-to-genomic alignment program ERK2 (MAPK1) variant 1 has 8 exons, the sizes being 119, 183, 190, 117, 115, 132, 110, 117 bps (mRNA coordinates).
Transcription Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene.
Pseudogene No pseudogenes have been reported for ERK2 (MAPK1).


Note ERK2 (MAPK1) is identified by the specific TEY (Thr-Glu-Tyr) sequence in the activation loop. ERK2 (MAPK1) is activated by dual phosphorylation of tyrosine (Tyr185) and threonine (Thr183) residues which is required for complete activation of the protein. Activated ERK2 (MAPK1) migrates into the nucleus and phosphorylates transcription factors.
Description ERK2 (MAPK1) is a 41 kDa protein consisting of 360 amino acids. ERK2 (MAPK1) protein is 85% identical to ERK1 (MAPK3) (another MAP kinase family member) and the two proteins have even higher, levels of similarity in their substrate binding regions. ERK2 (MAPK1) possess an acidic patch on the surface-exposed loop L16 of the kinase opposite to its catalytic cleft, which acts as a MAP kinase conserved docking motif (CD site; residues 310-325) which can also be found on activators (MAPKK), inhibitors (PTP-SL (PTPRR) and dual specificity phosphatases) and substrates (ELK-1).
Expression Ubiquitously expressed with varying levels in different tissues.
Localisation Subcellular location of ERK2 (MAPK1) protein is the cytoplasm, and the nucleus. Upon activation by dual phosphorylation on its Tyr and Thr residues by upstream kinases, ERK2 (MAPK1) is translocated into the nucleus from cytoplasm where it phosphorylates its nuclear targets.
Function Being one of the most studied cytoplasmic signaling pathways, the ERK pathway is activated via GTP-loading of RAS at the plasma membrane and sequential activation of a series of protein kinases. Activated RAS recruits the RAF family of kinases such as RAF1 to the plasma membrane which in turn acts as a MAPKKK and activates MAP kinase/ERK kinase 1 and 2 (MEK1 (MAP2K1) and MEK2 (MAP2K2)) by serine phosphorylation. MEK1/2 catalyze the phosphorylation of ERK1 (MAPK3) and ERK2 (MAPK1). Activated ERK1/2 (MAPK3/1) phosphorylates many different substrates involved in various cellular responses from cytoskeletal changes to gene transcription.
It has been shown that activation of ERK1/2 (MAPK3/1) is crucial for cyclin D1 induction, providing a molecular link between ERK signaling and cell cycle control as cyclin D1 gene is essential for G1 to S-phase progression.
In response to Angiotensin II, ERK1/2 (MAPK3/1) regulates cell proliferation by either one of two signaling pathways which are heterotrimeric G protein/PKC zeta-dependent signaling and SRC/YES1/FYN signaling. ERK1/2 (MAPK3/1) phosphorylates specific transcription factors ELK-1 (leading to c-FOS transcriptional activity) following its translocation into the nucleus due to heterotrimeric G protein/PKC zeta-dependent signaling. Due to its phosphorylation in the cytoplasm by SRC/YES1/FYN signaling, ERK1/2 complexes with RSK2 (RPS6KA), which in turn becomes activated and translocates into the nucleus to modulate c-FOS transcription and c-FOS protein activity.
The ERK pathway has been found to be responsible for the phosphorylation of BCL2 that contributes to cell survival, the suppression of the apoptotic effect of BAD, the up-regulation of the antiapoptotic protein MCL-1. Moreover, it has been also shown that ERK1/2 is one of the regulators of TP53 protein accumulation and activation during the DNA damage response.
ERK1/2 induces expression of PAI-1 (plasminogen activator type-1 inhibitor) which is closely associated with dynamic changes in cellular morphology and shape-altering physiologic processes.
CIITA is a critical transcription factor for the initiation of the expression of MHC class II genes and their subsequent induction of the immune response. Studies have indicated that ERK1/2 (MAPK3/1) negatively regulates CIITA by blocking expression of the CIITA gene and/or by phosphorylating CIITA at residues including serine 288, resulting in the loss of CIITA transactivation potential by enabling it to interact with CRM1 (XPO1) which causes export of CIITA protein from the nucleus.
Homology - P. troglodytes, mitogen-activated protein kinase 1, MAPK1
- C. lupus familiaris, mitogen-activated protein kinase 1, MAPK1
- B. taurus, mitogen-activated protein kinase 1, MAPK1
- M. musculus, mitogen-activated protein kinase 1, MAPK1
- R. norvegicus, mitogen-activated protein kinase 1, MAPK1
- G. gallus, mitogen-activated protein kinase 1, MAPK1
- D. rerio, mitogen-activated protein kinase 1, MAPK1
- D. melanogaster, rl, rolled
- A. gambiae, AgaP_AGAP009207, AGAP009207-PA
- C. elegans, mpk-1, MAP Kinase
- S. cerevisiae, KSS1, Kss1p
- K. lactis, KLLA0A02497g, hypothetical protein
- E. gossypii, AGOS_ACL191C, ACL191Cp
- O. sativa, Os02g0148100, hypothetical protein
- O. sativa, Os06g0699400, hypothetical protein
- P. falciparum, PF11_0147, mitogen-activated protein kinase 2

Implicated in

Entity Various diseases
Disease Although ERK1-/- mice are not embryonic lethal, ERK2-/- mice are. Thus, the ERK2 protein appears to be essential for viability; although dysregulation of the gene/protein expression has been implicated in a number of diseases. Specifically,ERK2 was found to be activated (phosphorylated) in the presence of aspirin triggered lipoxin (ATL-1), a molecule needed for the resolution of inflammation. The activated ERK2 resulted in the survival of mononuclear phagocytes which then exhibit nonphlogistic activities. Additionally, ERK2, but not ERK1, was shown to be constitutively activated by BCR/ABL1 in chronic myelogenous leukemia and implicated in the acquired resistance to imatinib mesylate.
Oncogenesis Elevated and constitutive activation of ERK1/2 has been detected in a large number of human tumors; including colon, kidney, gastric, prostate, breast, non-small cell lung cancer, bladder, chondrosarcomas and glioblastoma multiforme which show especially high frequencies of kinase activation. The reason for constitutive activation of the ERK pathway in the majority of tumor cells seems to be due to a disorder in RAF, RAS, EGFR or other upstream signaling molecules. In addition, several studies have shown that the ERK-MAPK pathway can directly promote cell motility and the migration of tumor cells.
Entity Gastric cancer
Note Epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR (PLAUR)) are elevated in human gastric cancers and it has been shown that uPAR expression is induced by EGF via ERK1/2 as well as AP-1 (JUN) and NF-kB signaling pathways which in turn, stimulates cell invasiveness in human gastric cancer AGS cells.
Entity Breast cancer
Note In breast cancer patients, ERK1/2 has been found to be heavily phosphorylated on tyrosyl residues and have a 5-10 fold elevated activity compared to benign conditions (fibroadenoma and fibrocystic disease). Localization studies showed that hyperexpressed ERK1/2 mRNA localized to malignant epithelial cells. Furthermore, hyperexpression of ERK1/2 mRNA (5-20 fold) was also observed in metastatic cells within the lymph nodes of breast cancer patients. In addition, in a recent study it was also shown that phosphorylated ERK1/2 levels were significantly high in breast cancer cell lines with high metastatic potential compared to non metastatic breast cancer cell lines. Beta-catenin, cyclin D1, and survivin have been shown to be downstream effectors of pERK1/2, while G1/0 proteins, phospholipase C, and protein kinase C serve as upstream activators of pERK1/2 in those cells.
Entity Colorectal cancer
Note Several lines of evidence indicate that overexpression and activation of ERK-MAPK pathway play an important part in progression of colorectal cancer. The constitutive activation of the RAF/MEK/ERK has been shown to be necessary for RAS-induced transformation of HT1080 human colon carcinoma cell line.
Entity Non-small-cell lung cancer
Note It has been found that nuclear and cytoplasmic ERK1/2 activation positively correlates with the stage and lymph node metastases in lung cancer. Therefore ERK1/2 is associated with advanced and aggressive NSCLC tumors.
Entity Bladder cancer
Note ERK1/2 has been shown to mediate TNF-alpha-induced MMP-9 expression by regulating the binding activity of the transcription factors, NF-kB, AP-1 and SP-1, in urinary bladder cancer HT1376 cells.
Entity Glioblastoma multiforme
Note The activation of ERK1/2 has been implicated in different pathobiological processes of GBM which is the most common and malignant brain tumor. The ERK1/2 activation has been linked to EGFR overexpression and hypermethylation of 9p21 locus.
Entity Prostate cancer
Note In prostate tumors, the level of activated MAP kinase were found to be increased with increasing Gleason score and tumor stage while nonneoplastic prostate tissue showed little or no staining with activated MAP kinase antiserum.
Entity Kidney cancer
Note In a high number of human renal cancers ERK1/2 has been found to be constitutively activated. Moreover, ERK1/2 activation was observed more frequently with high-grade renal cancer cells (RCC) compared to low-grade RCC.
Entity Chondrosarcomas
Note Activation of the JNK (MAPK8) and ERK signal transduction pathways have been shown to increase the activity and expression levels of their downstream effectors, transcription factors AP-1 and RUNX2. These transcription factors, in turn, stimulate genes that are involved in chondroblast cell biology, ultimately inducing chondroblastic tumorigenesis.
Entity Cardiac hypertrophy
Note It has been implicated that ERK1/2 mediate cardiac hypertrophy, which is a major risk factor for the development of arrhythmias, heart failure and sudden death.


ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.
Aceves-Luquero CI, Agarwal A, Callejas-Valera JL, Arias-Gonzalez L, Esparis-Ogando A, del Peso Ovalle L, Bellon-Echeverria I, de la Cruz-Morcillo MA, Galan Moya EM, Moreno Gimeno I, Gomez JC, Deininger MW, Pandiella A, Sanchez Prieto R.
PLoS One. 2009 Jul 1;4(7):e6124.
PMID 19568437
EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells.
Baek MK, Kim MH, Jang HJ, Park JS, Chung IJ, Shin BA, Ahn BW, Jung YD.
Oncol Rep. 2008 Dec;20(6):1569-75.
PMID 19020743
The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis.
Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, Dani C, Hofman P, Pages G, Pouyssegur J, Le Marchand-Brustel Y, Binetruy B.
Diabetes. 2005 Feb;54(2):402-11.
PMID 15677498
Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase.
Camp HS, Tafuri SR.
J Biol Chem. 1997 Apr 18;272(16):10811-6.
PMID 9099735
The MAPK signalling pathways and colorectal cancer.
Fang JY, Richardson BC.
Lancet Oncol. 2005 May;6(5):322-7. (REVIEW)
PMID 15863380
Activation of mitogen-activated protein kinase associated with prostate cancer progression.
Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ.
Cancer Res. 1999 Jan 15;59(2):279-84.
PMID 9927031
ERK1/2 regulates ANG II-dependent cell proliferation via cytoplasmic activation of RSK2 and nuclear activation of elk1.
Godeny MD, Sayeski PP.
Am J Physiol Cell Physiol. 2006 Dec;291(6):C1308-17. Epub 2006 May 24.
PMID 16723511
Promoter analysis of the human p44 mitogen-activated protein kinase gene (MAPK3): transcriptional repression under nonproliferating conditions.
Hernandez R, Garcia F, Encio I, De Miguel C.
Genomics. 2004 Jul;84(1):222-6.
PMID 15203221
Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors.
Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M.
Oncogene. 1999 Jan 21;18(3):813-22.
PMID 9989833
Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
Lavoie JN, L'Allemain G, Brunet A, Muller R, Pouyssegur J.
J Biol Chem. 1996 Aug 23;271(34):20608-16.
PMID 8702807
The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFR amplification.
Lopez-Gines C, Gil-Benso R, Benito R, Mata M, Pereda J, Sastre J, Roldan P, Gonzalez-Darder J, Cerda-Nicolas M.
Neuropathology. 2008 Oct;28(5):507-15. Epub 2008 Apr 10.
PMID 18410277
Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling.
Lorenz K, Schmitt JP, Vidal M, Lohse MJ.
Int J Biochem Cell Biol. 2009 Dec;41(12):2351-5. Epub 2009 Aug 8.
PMID 19666137
In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms.
Mandell JW, Hussaini IM, Zecevic M, Weber MJ, VandenBerg SR.
Am J Pathol. 1998 Nov;153(5):1411-23.
PMID 9811332
Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII.
Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID.
J Biol Chem. 2007 May 18;282(20):15208-16. Epub 2007 Mar 29.
PMID 17395590
Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma.
Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T, Okada Y, Kawaichi M, Kohno M, Yoshida O.
Cancer Res. 1995 Sep 15;55(18):4182-7.
PMID 7664295
The MAPK-AP-1/-Runx2 signalling axes are implicated in chondrosarcoma pathobiology either independently or via up-regulation of VEGF.
Papachristou DJ, Papachristou GI, Papaefthimiou OA, Agnantis NJ, Basdra EK, Papavassiliou AG.
Histopathology. 2005 Dec;47(6):565-74. Erratum in: Histopathology. 2006 Feb;48(3):323. Papachristou, GJ [corrected to Papachristou, GI].
PMID 16324193
Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions.
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH.
Endocr Rev. 2001 Apr;22(2):153-83. (REVIEW)
PMID 11294822
Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin.
Persons DL, Yazlovitskaya EM, Pelling JC.
J Biol Chem. 2000 Nov 17;275(46):35778-85.
PMID 10958792
An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development.
Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, Ang SL, Meloche S.
EMBO Rep. 2003 Oct;4(10):964-8. Epub 2003 Sep 19.
PMID 14502223
MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks.
Samarakoon R, Higgins PJ.
J Cell Sci. 2002 Aug 1;115(Pt 15):3093-103.
PMID 12118065
The MAPK signaling cascade.
Seger R, Krebs EG.
FASEB J. 1995 Jun;9(9):726-35. (REVIEW)
PMID 7601337
A synthetic analog of 15-epi-lipoxin A4 inhibits human monocyte apoptosis: involvement of ERK-2 and PI3-kinase.
Simoes RL, Niconi-de-Almeida Y, da-Fe AR, Barja-Fidalgo C, Fierro IM.
Prostaglandins Other Lipid Mediat. 2010 Feb;91(1-2):10-7. Epub 2009 Dec 29.
PMID 20004734
Hyperexpression of mitogen-activated protein kinase in human breast cancer.
Sivaraman VS, Wang H, Nuovo GJ, Malbon CC.
J Clin Invest. 1997 Apr 1;99(7):1478-83.
PMID 9119990
Two clusters of residues at the docking groove of mitogen-activated protein kinases differentially mediate their functional interaction with the tyrosine phosphatases PTP-SL and STEP.
Tarrega C, Blanco-Aparicio C, Munoz JJ, Pulido R.
J Biol Chem. 2002 Jan 25;277(4):2629-36. Epub 2001 Nov 15.
PMID 11711538
ERK2 shows a restrictive and locally selective mechanism of recognition by its tyrosine phosphatase inactivators not shared by its activator MEK1.
Tarrega C, Rios P, Cejudo-Marin R, Blanco-Aparicio C, van den Berk L, Schepens J, Hendriks W, Tabernero L, Pulido R.
J Biol Chem. 2005 Nov 11;280(45):37885-94. Epub 2005 Sep 7.
PMID 16148006
ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours.
Vicent S, Lopez-Picazo JM, Toledo G, Lozano MD, Torre W, Garcia-Corchon C, Quero C, Soria JC, Martin-Algarra S, Manzano RG, Montuenga LM.
Br J Cancer. 2004 Mar 8;90(5):1047-52.
PMID 14997206
Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator.
Voong LN, Slater AR, Kratovac S, Cressman DE.
J Biol Chem. 2008 Apr 4;283(14):9031-9. Epub 2008 Feb 1.
PMID 18245089


This paper should be referenced as such :
Tuncay, S ; Banerjee, S
MAPK1 (mitogen-activated protein kinase 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(10):986-989.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
  Lymphomatoid papulosis (LyP) with 6p25.3 rearrangement DUSP22 and IRF4/
t(6;7)(p25.3;q32.3) DUSP22/FRA7H

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 6 ]
  Skin: Melanoma
t(6;22)(p24;q11) HIVEP1/MAPK1
t(13;22)(q34;q11) MAPK1/ARHGEF7
CRKL/MAPK1 (22q11)
MAPK1/TOP3B (22q11)
t(22;22)(q11;q13) MAPK1/KCNJ4

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)5594
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 18 17:42:14 CEST 2018

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