MAPK3 (mitogen-activated protein kinase 3)
2010-01-01 Seda Tuncay , Sreeparna Banerjee AffiliationDepartment of Biological Sciences, Middle East Technical University, Ankara 06531, Turkey
Identity
HGNC
LOCATION
16p11.2
LOCUSID
ALIAS
ERK-1,ERK1,ERT2,HS44KDAP,HUMKER1A,P44ERK1,P44MAPK,PRKM3,p44-ERK1,p44-MAPK
FUSION GENES
DNA/RNA
Diagram of the ERK1 (MAPK3) 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 MAPK3 gene maps to NC_000016.9 and spans a region of 9.21 kb. According to Spidey mRNA-to-genomic alignment program ERK1 (MAPK3) variant 1 (the most common variant) has 8 exons, the sizes being 170, 183, 190, 117, 115, 132, 110, 123 bps (mRNA coordinates).
Transcription
The promoter analysis of the human MAPK3 has shown that the elements responsible for basal transcriptional activity are located within 200 bp upstream of the initiation codon in the 5 UTR and rich in G/C content (80.5%). The sequence has four SP1 sites and an E box as the most relevant motifs. Site-directed mutagenesis, EMSA, and DNase I footprinting experiments proved that all these elements are required to achieve a significant level of transcription. It has also been reported that the promoter activity is strongly repressed when the cells are grown under growth arrest conditions, such as confluence or serum withdrawal.
Pseudogene
No pseudogenes have been reported for MAPK3.
Proteins
Note
ERK1 (MAPK3) is identified by the specific TEY (Thr-Glu-Tyr) sequence in its activation loop. ERK1 (MAPK3) is activated by dual phosphorylation of tyrosine (Tyr204) and threonine (Thr202) residues which is required for complete activation of the protein. Activated ERK1 (MAPK3) migrates into the nucleus and phosphorylates transcription factors.
Description
ERK1 (MAPK3) is a 43 kDa protein consisting of 379 amino acids. ERK1 (MAPK3) protein is 85% identical to ERK2 (MAPK1) (another MAP kinase family member) and the two proteins have even higher levels of similarity in their substrate binding regions. ERK1 (MAPK3) and ERK2 (MAPK1) both possess 2 DXXD docking sites that provide interaction sites with a Kinase Interaction Motif (KIM), which can 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 ERK1 (MAPK3) protein is the cytoplasm, and the nucleus. Upon activation by dual phosphorylation on its Tyr and Thr residues by upstream kinases, ERK1 (MAPK3) 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. ERK1 (MAPK3) was initially identified as an insulin-stimulated protein kinase which has an activity towards microtubule-associated protein-2. Today, it is well known that ERK1/2 (MAPK3/1) is especially involved in the control of cell proliferation, cell differentiation and cell survival.
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 (MAPK3/1) 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 (MAPK3/1) is one of the regulators of TP53 protein accumulation and activation during the DNA damage response.
ERK1/2 (MAPK3/1) 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.
ERK1/2 (MAPK3/1) has been shown to regulate PPARg1 following EGF stimulation.
CIITA is a critical transcription factor that initiates the expression of MHC class II genes and the 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 (MAPK3/1) 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 (MAPK3/1) is one of the regulators of TP53 protein accumulation and activation during the DNA damage response.
ERK1/2 (MAPK3/1) 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.
ERK1/2 (MAPK3/1) has been shown to regulate PPARg1 following EGF stimulation.
CIITA is a critical transcription factor that initiates the expression of MHC class II genes and the 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, MAPK3, mitogen-activated protein kinase 3
- C. lupus familiaris, MAPK3, mitogen-activated protein kinase 3
- B. taurus, MAPK3, mitogen-activated protein kinase 3
- M. musculus, MAPK3, mitogen-activated protein kinase 3
- R. norvegicus, MAPK3, mitogen activated protein kinase 3
- D. rerio, MAPK3, mitogen-activated protein kinase 3
- S. pombe, spk1, MAP kinase Spk1
- S. cerevisiae, FUS3, Fus3p
- K. lactis, KLLA0E10527g, hypothetical protein
- E. gossypii, AGOS_AFR019W, AFR019Wp
- M. grisea, MGG_09565, mitogen-activated protein kinase
- N. crassa, NCU02393.1, hypothetical protein ((AF348490) MAP kinase [Neurospora crassa OR74A])
- A. thaliana, ATMPK13, ATMPK13; MAP kinase/ kinase
- C. lupus familiaris, MAPK3, mitogen-activated protein kinase 3
- B. taurus, MAPK3, mitogen-activated protein kinase 3
- M. musculus, MAPK3, mitogen-activated protein kinase 3
- R. norvegicus, MAPK3, mitogen activated protein kinase 3
- D. rerio, MAPK3, mitogen-activated protein kinase 3
- S. pombe, spk1, MAP kinase Spk1
- S. cerevisiae, FUS3, Fus3p
- K. lactis, KLLA0E10527g, hypothetical protein
- E. gossypii, AGOS_AFR019W, AFR019Wp
- M. grisea, MGG_09565, mitogen-activated protein kinase
- N. crassa, NCU02393.1, hypothetical protein ((AF348490) MAP kinase [Neurospora crassa OR74A])
- A. thaliana, ATMPK13, ATMPK13; MAP kinase/ kinase
Implicated in
Entity name
Various diseases
Disease
Although both ERK1 (MAPK3) and ERK2 (MAPK1) have very similar functions, ERK2-/- mice are embryonic lethal while ERK1-/- mice are viable and show normal size and fertility. Thus each isoform may have a unique role, or there may be threshold of total ERK activity for normal viability.
Although viable, ERK1-/- mice have reduced ability for thymocyte maturation and proliferation when T cell receptors are activated. These mice also show an enhancement of long term memory that was shown to be dependent on the striatum. Additionally, the loss of ERK1 results in a loss of adipocity, with the mice having fewer adipocytes than the wild type counterparts.
Although viable, ERK1-/- mice have reduced ability for thymocyte maturation and proliferation when T cell receptors are activated. These mice also show an enhancement of long term memory that was shown to be dependent on the striatum. Additionally, the loss of ERK1 results in a loss of adipocity, with the mice having fewer adipocytes than the wild type counterparts.
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 |
|---|---|---|---|
| 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 |
| 1846291 | 1991 | Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase. | Boulton TG 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 |
| 18983981 | 2008 | Crystal structure of human mono-phosphorylated ERK1 at Tyr204. | Kinoshita T 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 |
| 12062026 | 2002 | Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. | Mazzucchelli C 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 |
| 10558995 | 1999 | Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. | Pagès G 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 |
| 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 |
| 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: 5595
MIM: 601795
HGNC: 6877
Ensembl: ENSG00000102882
Variants:
dbSNP: 5595
ClinVar: 5595
TCGA: ENSG00000102882
COSMIC: MAPK3
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 | |||
| PA338 | STAT5A | Gene | Pathway | associated | |||
| PA36042 | SP1 | Gene | Pathway | associated | |||
| PA36183 | STAT1 | Gene | Pathway | associated | |||
| PA36184 | STAT2 | Gene | Pathway | associated | |||
| PA36185 | STAT4 | Gene | Pathway | associated | |||
| PA36186 | STAT5B | Gene | Pathway | associated | |||
| PA62 | ATP1A1 | Gene | Pathway | associated | 23788015 | ||
| PA7000 | sorafenib | Chemical | Pathway | associated | 20124951 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 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 |
| 38242328 | 2024 | AKAP2-anchored extracellular signal-regulated kinase 1 (ERK1) regulates cardiac myofibroblast migration. | 0 |
| 38301910 | 2024 | PP4R1 promotes glycolysis and gallbladder cancer progression through facilitating ERK1/2 mediated PKM2 nuclear translocation. | 0 |
| 38581859 | 2024 | ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2. | 0 |
| 38725848 | 2024 | Ciliogenesis-associated Kinase 1 Promotes Breast Cancer Cell Proliferation and Chemoresistance via Phosphorylating ERK1. | 0 |
| 38885209 | 2024 | Ferroptosis-related gene MAPK3 is associated with the neurological outcome after cardiac arrest. | 0 |
| 38993552 | 2024 | Deubiquitination of CIB1 by USP14 promotes lenvatinib resistance via the PAK1-ERK1/2 axis in hepatocellular carcinoma. | 0 |
| 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 |
| 38242328 | 2024 | AKAP2-anchored extracellular signal-regulated kinase 1 (ERK1) regulates cardiac myofibroblast migration. | 0 |
| 38301910 | 2024 | PP4R1 promotes glycolysis and gallbladder cancer progression through facilitating ERK1/2 mediated PKM2 nuclear translocation. | 0 |
| 38581859 | 2024 | ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2. | 0 |
| 38725848 | 2024 | Ciliogenesis-associated Kinase 1 Promotes Breast Cancer Cell Proliferation and Chemoresistance via Phosphorylating ERK1. | 0 |
| 38885209 | 2024 | Ferroptosis-related gene MAPK3 is associated with the neurological outcome after cardiac arrest. | 0 |
Citation
Seda Tuncay ; Sreeparna Banerjee
MAPK3 (mitogen-activated protein kinase 3)
Atlas Genet Cytogenet Oncol Haematol. 2010-01-01
Online version: http://atlasgeneticsoncology.org/gene/425/mapk3-(mitogen-activated-protein-kinase-3)
