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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)

Identity

Other aliasEC 2.7.11.24
ERK
ERK-2
ERK2
ERT1
MAPK2
P42MAPK
PRKM1
PRKM2
p38
p40
p41
p41mapk
p42-MAPK
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:
centromere
- 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
telomere
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)

DNA/RNA

 
  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).

Protein

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
- A. thaliana, ATMPK2, ATMPK2 (ARABIDOPSIS THALIANA MITOGE...)
- A. thaliana, ATMPK1, ATMPK1 (MITOGEN-ACTIVATED PROTEIN K...)
- O. sativa, Os02g0148100, hypothetical protein
- O. sativa, Os06g0699400, hypothetical protein
- P. falciparum, PF11_0147, mitogen-activated protein kinase 2

Implicated in

Note
  
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.
  

Bibliography

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Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors.
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Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
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Citation

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 : http://AtlasGeneticsOncology.org/Genes/MAPK1ID41288ch22q11.html


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

Nomenclature
Cards
AtlasMAPK1ID41288ch22q11.txt
Aliases
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
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
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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