MAPK1 (mitogen-activated protein kinase 1)
2010-01-01 Seda Tuncay , Sreeparna Banerjee AffiliationDepartment of Biological Sciences, Middle East Technical University, Ankara 06531, Turkey
Identity
HGNC
LOCATION
22q11.21
LOCUSID
ALIAS
ERK,ERK-2,ERK2,ERT1,MAPK2,NS13,P42MAPK,PRKM1,PRKM2,p38,p40,p41,p41mapk,p42-MAPK
FUSION GENES
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).
Proteins
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.
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
- 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
Entity name
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 name
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 name
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 name
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 name
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 name
Bladder cancer
Note
Entity name
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 name
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 name
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 name
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 name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 19568437 | 2009 | ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy. | Aceves-Luquero CI et al |
| 19020743 | 2008 | EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. | Baek MK et al |
| 15677498 | 2005 | The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. | Bost F et al |
| 9099735 | 1997 | Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase. | Camp HS et al |
| 15863380 | 2005 | The MAPK signalling pathways and colorectal cancer. | Fang JY et al |
| 9927031 | 1999 | Activation of mitogen-activated protein kinase associated with prostate cancer progression. | Gioeli D et al |
| 16723511 | 2006 | ERK1/2 regulates ANG II-dependent cell proliferation via cytoplasmic activation of RSK2 and nuclear activation of elk1. | Godeny MD et al |
| 15203221 | 2004 | Promoter analysis of the human p44 mitogen-activated protein kinase gene (MAPK3): transcriptional repression under nonproliferating conditions. | Hernández R et al |
| 9989833 | 1999 | Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. | Hoshino R et al |
| 8702807 | 1996 | Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. | Lavoie JN et al |
| 18410277 | 2008 | The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFR amplification. | Lopez-Gines C et al |
| 19666137 | 2009 | Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. | Lorenz K et al |
| 9811332 | 1998 | In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms. | Mandell JW et al |
| 17395590 | 2007 | Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. | Nikodemova M et al |
| 7664295 | 1995 | Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. | Oka H et al |
| 16324193 | 2005 | The MAPK-AP-1/-Runx2 signalling axes are implicated in chondrosarcoma pathobiology either independently or via up-regulation of VEGF. | Papachristou DJ et al |
| 11294822 | 2001 | Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. | Pearson G et al |
| 10958792 | 2000 | Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. | Persons DL et al |
| 14502223 | 2003 | An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. | Saba-El-Leil MK et al |
| 12118065 | 2002 | 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 et al |
| 7601337 | 1995 | The MAPK signaling cascade. | Seger R et al |
| 20004734 | 2010 | A synthetic analog of 15-epi-lipoxin A4 inhibits human monocyte apoptosis: involvement of ERK-2 and PI3-kinase. | Simões RL et al |
| 9119990 | 1997 | Hyperexpression of mitogen-activated protein kinase in human breast cancer. | Sivaraman VS et al |
| 11711538 | 2002 | 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. | Tárrega C et al |
| 16148006 | 2005 | ERK2 shows a restrictive and locally selective mechanism of recognition by its tyrosine phosphatase inactivators not shared by its activator MEK1. | Tárrega C et al |
| 14997206 | 2004 | ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. | Vicent S et al |
| 18245089 | 2008 | Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator. | Voong LN et al |
Other Information
Locus ID:
NCBI: 5594
MIM: 176948
HGNC: 6871
Ensembl: ENSG00000100030
Variants:
dbSNP: 5594
ClinVar: 5594
TCGA: ENSG00000100030
COSMIC: MAPK1
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA248 | NFKB1 | Gene | Pathway | associated | |||
| PA27749 | ELK1 | Gene | Pathway | associated | |||
| PA27902 | ETS1 | Gene | Pathway | associated | |||
| PA28212 | FOS | Gene | Pathway | associated | |||
| PA284 | MAP2K7 | Gene | Pathway | associated | 20124951 | ||
| PA296 | RELA | Gene | Pathway | associated | |||
| PA30006 | JUN | Gene | Pathway | associated | |||
| PA30584 | MAP2K1 | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA30587 | MAP2K2 | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA30588 | MAP2K3 | Gene | Pathway | associated | 20124951 | ||
| PA30589 | MAP2K4 | Gene | Pathway | associated | 20124951 | ||
| PA30590 | MAP2K5 | Gene | Pathway | associated | 20124951 | ||
| PA30591 | MAP2K6 | Gene | Pathway | associated | 20124951 | ||
| PA31353 | MYC | Gene | Pathway | associated | |||
| PA31600 | NFKB2 | Gene | Pathway | associated | |||
| PA337 | STAT3 | Gene | Pathway | associated | |||
| PA33748 | PRKACA | Gene | Pathway | associated | |||
| PA33749 | PRKACB | Gene | Pathway | associated | |||
| PA33750 | PRKACG | Gene | Pathway | associated | |||
| PA338 | STAT5A | Gene | Pathway | associated | |||
| PA36042 | SP1 | Gene | Pathway | associated | |||
| PA36111 | SRC | Gene | Pathway | associated | |||
| PA36183 | STAT1 | Gene | Pathway | associated | |||
| PA36184 | STAT2 | Gene | Pathway | associated | |||
| PA36185 | STAT4 | Gene | Pathway | associated | |||
| PA36186 | STAT5B | Gene | Pathway | associated | |||
| PA40 | GRK2 | Gene | Pathway | associated | |||
| PA41 | GRK3 | Gene | Pathway | associated | |||
| PA59 | ARRB1 | Gene | Pathway | associated | |||
| PA60 | ARRB2 | Gene | Pathway | associated | |||
| PA62 | ATP1A1 | Gene | Pathway | associated | 23788015 | ||
| PA7000 | sorafenib | Chemical | Pathway | associated | 20124951 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37041423 | 2024 | miR-4529-3p Promotes the Progression of Retinoblastoma by Inhibiting RB1 Expression and Activating the ERK Signaling Pathway. | 0 |
| 37237135 | 2024 | ERK/PKM2 Is Mediated in the Warburg Effect and Cell Proliferation in Arsenic-Induced Human L-02 Hepatocytes. | 0 |
| 37260124 | 2024 | LncRNA PVT1 inhibits endothelial cells apoptosis in coronary heart disease through regulating MAPK1 expression via miR-532-3p. | 0 |
| 37318032 | 2024 | miR-200a-3p regulates epithelial-mesenchymal transition and inflammation in chronic rhinosinusitis with nasal polyps by targeting ZEB1 via ERK/p38 pathway. | 0 |
| 37462532 | 2024 | Leukocyte Ig-like receptor A3 facilitates inflammation, migration and invasion of synovial tissue-derived fibroblasts via ERK/JNK activation. | 1 |
| 38048919 | 2024 | Progestins and breast cancer hallmarks: The role of the ERK1/2 and JNK pathways in estrogen receptor positive breast cancer cells. | 0 |
| 38141769 | 2024 | LncNFYB promotes the proliferation of rheumatoid arthritis fibroblast-like synoviocytes via LncNFYB/ANXA2/ERK1/2 axis. | 0 |
| 38169625 | 2024 | MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent Mechanism. | 0 |
| 38181585 | 2024 | FNDC4 reduces inflammation, proliferation, invasion and migration of rheumatoid synovial cells by inhibiting CCL2/ERK signaling. | 0 |
| 38216090 | 2024 | EID3 inhibits the osteogenic differentiation of periodontal ligament stem cells and mediates the signal transduction of TAZ-EID3-AKT/MTOR/ERK. | 0 |
| 38261743 | 2024 | IL-17 promotes IL-18 production via the MEK/ERK/miR-4492 axis in osteoarthritis synovial fibroblasts. | 0 |
| 38301910 | 2024 | PP4R1 promotes glycolysis and gallbladder cancer progression through facilitating ERK1/2 mediated PKM2 nuclear translocation. | 0 |
| 38430029 | 2024 | Circ-LDLRAD3/miR-655-3p/MAPK1 axis enhances cell migration and invasion in papillary thyroid carcinoma. | 0 |
| 38466834 | 2024 | Inhibition of HSP20 Ameliorates Steatotic Liver Disease by Stimulating ERK2-Dependent Autophagy. | 0 |
| 38581859 | 2024 | ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2. | 0 |
Citation
Seda Tuncay ; Sreeparna Banerjee
MAPK1 (mitogen-activated protein kinase 1)
Atlas Genet Cytogenet Oncol Haematol. 2010-01-01
Online version: http://atlasgeneticsoncology.org/gene/41288
