Alternative titles; symbols
HGNC Approved Gene Symbol: MAPK1
Cytogenetic location: 22q11.22 Genomic coordinates (GRCh38) : 22:21,759,657-21,867,680 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.22 | Noonan syndrome 13 | 619087 | Autosomal dominant | 3 |
Boulton et al. (1991) cloned 2 rat enzymes that are S6 kinases and a third related kinase and named them extracellular signal-regulated kinase (Erk)-1, -2, and -3.
Owaki et al. (1992) isolated cDNAs for human ERK1 (MAPK3; 601795) and ERK2. The deduced 360-amino acid human ERK2 protein shares 98% identity with rat Erk2.
By a combination of fluorescence in situ hybridization and Southern blot analysis of genomic DNA from a panel of human/hamster cell hybrids, Li et al. (1994) mapped the MAPK1 gene to 22q11.2. Saba-El-Leil et al. (1997) mapped the mouse Mapk1 gene to chromosome 16, in a region showing homology of synteny with human 22q11.2.
ERKs are also known as maturation- or mitogen-activated protein (MAP) kinases. Cobb et al. (1991) provided a review. Thomas (1992) gave a review of MAP kinases and Seger and Krebs (1995) reviewed the MAP kinase signaling cascade.
The MAP kinase ERK2 is widely involved in eukaryotic signal transduction. Upon activation, it translocates to the nucleus of the stimulated cell, where it phosphorylates nuclear targets. Khokhlatchev et al. (1998) found that nuclear accumulation of microinjected ERK2 depends on its phosphorylation state rather than on its activity or on upstream components of its signaling pathway. Phosphorylated ERK2 forms dimers with phosphorylated and unphosphorylated ERK2 partners. Disruption of dimerization by mutagenesis of ERK2 reduces its ability to accumulate in the nucleus, suggesting that dimerization is essential for its normal ligand-dependent relocalization. Other MAP kinase family members also form dimers. Khokhlatchev et al. (1998) concluded that dimerization is part of the mechanism of action of the MAP kinase family.
Influenza A viruses are significant causes of morbidity and mortality worldwide. Annually updated vaccines may prevent disease, and antivirals are effective treatment early in disease when symptoms are often nonspecific. Viral replication is supported by intracellular signaling events. Using U0126, a nontoxic inhibitor of MEK1 (176872) and MEK2 (601263), and thus an inhibitor of the RAF1 (164760)/MEK/ERK pathway (see Favata et al. (1998)), Pleschka et al. (2001) examined the cellular response to infection with influenza A. U0126 suppressed both the early and late ERK activation phases after virus infection. Inhibition of the signaling pathway occurred without impairing the synthesis of viral RNA or protein, or the import of viral ribonucleoprotein complexes (RNP) into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the export of viral RNP without affecting the cellular mRNA export pathway. Pleschka et al. (2001) proposed that ERK regulates a cellular factor involved in the viral nuclear export protein function. They suggested that local application of MEK inhibitors may have only minor toxic effects on the host while inhibiting viral replication without giving rise to drug-resistant virus variants.
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 a 2-hybrid screen and in vitro association experiments, Waskiewicz et al. (1997) identified Mnk1 (MKNK1; 606724) and Mnk2 (MKNK2; 605069) as Erk2-binding proteins in mouse.
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 and/or MEK2. 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.
The MAP kinase 1,2/protein kinase C (see 176960) system is an intracellular signaling network that regulates many cellular machines, including the cell cycle machinery and autocrine/paracrine factor synthesizing machinery. Bhalla et al. (2002) used a combination of computational analysis and experiments in NIH-3T3 fibroblasts to understand the design principles of this controller network. Bhalla et al. (2002) found that the growth factor-stimulated signaling network controlled by MAPK 1,2/PKC can operate with 1 or 2 stable states. At low concentrations of MAPK phosphatase (600714), the system exhibits bistable behavior, such that brief stimulus results in sustained MAPK activation. The MAPK-induced increase in the amounts of MAPK phosphatase eliminates the prolonged response capability and moves the network to a monostable state, in which it behaves as a proportional response system responding acutely to stimuli. Thus, the MAPK 1,2/PKC controller network is flexibly designed, and MAPK phosphatase may be critical for this flexible response.
In rat neuronal cell cultures, Paul et al. (2003) showed that glutamate-mediated activation of N-methyl-D-aspartate (NMDA) receptors (see 138249) leads to the rapid but transient phosphorylation of ERK2. NMDA-mediated influx of calcium, but not increased intracellular calcium from other sources, led to activation of the calcium-dependent phosphatase calcineurin and the subsequent dephosphorylation and activation of the protein-tyrosine phosphatase STEP (176879). STEP then inactivated ERK2 through dephosphorylation of the tyrosine residue in its activation domain and blocked nuclear translocation of the kinase. Thus, STEP is important in regulating the duration of ERK activation and downstream signaling in neurons.
Chuderland et al. (2008) identified an SPS motif within the kinase domain of rodent Erk2 that was phosphorylated upon stimulation to induce nuclear Erk2 translocation. A 19-amino acid stretch containing the STS motif directed nuclear accumulation of a nonnuclear test protein. Immunoprecipitation analysis and small interfering RNA experiments in HeLa cells indicated that phosphorylation of ERK2 on the SPS motif caused nuclear ERK2 transport via release of ERK2 from the nuclear pore protein NUP153 (603948) and interaction of ERK2 with importin-7 (IPO7; 605586).
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 (601795) 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.
Using time-resolved nuclear magnetic resonance spectroscopy, Mylona et al. (2016) found that ERK2 phosphorylation proceeded at markedly different rates at 8 transcriptional activation domain (TAD) sites in vitro, which were classified as fast, intermediate, and slow. Mutagenesis experiments showed that phosphorylation of fast and intermediate sites promoted Mediator interaction and transcriptional activation, whereas modification of slow sites counteracted both functions, thereby limiting ELK1 output. Progressive ELK1 phosphorylation thus ensures a self-limiting response to ERK activation, which occurs independently of antagonizing phosphatase activity.
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 patients (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.
In 7 unrelated children who exhibited features consistent with Noonan syndrome (NS13; 619087), Motta et al. (2020) identified heterozygosity for de novo private missense mutations in the MAPK1 gene (see, e.g., 176948.0001-176948.0004). All 7 mutations showed gain-of-function effects. Screening of the MAPK1 gene in an additional 267 individuals with a clinically suspected diagnosis of RASopathy, who were negative for mutation in known RASopathy-associated genes, did not reveal other pathogenic variants.
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 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.
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.
Glutamine-103 in rat Erk2 is a gatekeeper residue that confers selectivity for binding nucleotides and small-molecule inhibitors. Emrick et al. (2006) found that mutation of glutamine-103 to alanine or glycine increased the basal kinase activity of Erk2 through autoactivation via enhanced autophosphorylation of regulatory tyrosine and threonine sites within the Erk2 activation lip that controls its kinase activity. Using hydrogen exchange, mass spectroscopy, steady-state kinetics, and mutagenesis, Emrick et al. (2006) determined that an N-terminal hydrophobic cluster that includes the gatekeeper forms a structural unit that functions to maintain the off state of ERK2 before cell signal activation.
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.
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-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.
Holm et al. (2011) showed that Erk1/2 and Smad2 (601366) are activated in a mouse model of Marfan syndrome (154700), 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.
In an 8-year-old Spanish boy (patient 7) with Noonan syndrome (NS13; 619087), Motta et al. (2020) identified heterozygosity for a de novo c.221T-A transversion (c.221T-A, NM_002745.4) in the MAPK1 gene, resulting in an ile74-to-asn (I74N) substitution at a highly conserved residue. The mutation was not found in the ExAC or gnomAD databases. MAPK phosphorylation assays in transfected HEK293 cells showed significantly increased phosphorylation with the I74N mutant compared to wildtype MAPK1, suggesting an activating role for the variant. Confocal laser scanning microscopy in Lenti-X 293T cells demonstrated more efficient nuclear translocation, and immunoblotting analysis revealed enhanced phosphorylation of known MAPK1 substrates with the mutant compared to wildtype protein, confirming MAPK signaling upregulation. In a C. elegans model, I74N mutants displayed a low-penetrant multivulva phenotype and partial rescue of the vulvaless phenotype, both to a greater degree than with wildtype MAPK1. Experiments using transiently transfected HEK293T cells indicated that the activating role of the I74N variant results at least in part from altered binding of the kinase with signaling partners, and demonstrated direct dependency of the mutant on MEK1 (MAP2K1; 176872) to drive upregulated signaling through the MPAK cascade.
In a 13-year-old Italian boy (patient 1) with Noonan syndrome (NS13; 619087), Motta et al. (2020) identified heterozygosity for a de novo c.521C-T transition (c.521C-T, NM_002745.4) in the MAPK1 gene, resulting in an ala174-to-val (A174V) substitution at a highly conserved residue within the activation segment. The mutation was not found in the ExAC or gnomAD databases. MAPK phosphorylation assays in transfected HEK293 cells showed significantly increased phosphorylation with the A174V mutant compared to wildtype MAPK1, suggesting an activating role for the variant. Confocal laser scanning microscopy in Lenti-X 293T cells demonstrated more efficient nuclear translocation, and immunoblotting analysis revealed enhanced phosphorylation of known MAPK1 substrates with the mutant compared to wildtype protein, confirming MAPK signaling upregulation. In a C. elegans model, A174V mutants displayed a low-penetrant multivulva phenotype and partial rescue of the vulvaless phenotype, both to a greater degree than with wildtype MAPK1. Experiments using transiently transfected HEK293T cells indicated that the activating role of the A174V variant results at least in part from altered binding of the kinase with signaling partners, and demonstrated direct dependency of the mutant on MEK1 (MAP2K1; 176872) to drive upregulated signaling through the MPAK cascade.
In a 17-year-old Dutch girl (patient 4) with Noonan syndrome (NS13; 619087), Motta et al. (2020) identified heterozygosity for a de novo c.952G-A transition (c.952G-A, NM_002745.4) in the MAPK1 gene, resulting in an asp318-to-asn (D318N) substitution at a highly conserved residue within the common docking domain. The mutation was not found in the ExAC or gnomAD databases. MAPK phosphorylation assays in transfected HEK293 cells showed significantly increased phosphorylation with the D318N mutant compared to wildtype MAPK1, suggesting an activating role for the variant. Confocal laser scanning microscopy in Lenti-X 293T cells demonstrated more efficient nuclear translocation, and immunoblotting analysis revealed enhanced phosphorylation of known MAPK1 substrates with the mutant compared to wildtype protein, confirming MAPK signaling upregulation. Experiments using transiently transfected HEK293T cells indicated that the activating role of the D318N variant results at least in part from altered binding of the kinase with signaling partners, and demonstrated direct dependency of the mutant on MEK1 (MAP2K1; 176872) to drive upregulated signaling through the MPAK cascade.
In a 12-year-old Italian boy (patient 2) with Noonan syndrome (NS13; 619087), Motta et al. (2020) identified heterozygosity for a de novo c.953A-G transition (c.953A-G, NM_002745.4) in the MAPK1 gene, resulting in an asp318-to-gly (D318G) substitution at a highly conserved residue within the common docking domain. The mutation was not found in the ExAC or gnomAD databases. MAPK phosphorylation assays in transfected HEK293 cells showed significantly increased phosphorylation with the D318G mutant compared to wildtype MAPK1, suggesting an activating role for the variant. Confocal laser scanning microscopy in Lenti-X 293T cells demonstrated more efficient nuclear translocation, and immunoblotting analysis revealed enhanced phosphorylation of known MAPK1 substrates with the mutant compared to wildtype protein, confirming MAPK signaling upregulation. In a C. elegans model, D318G mutants displayed a low-penetrant multivulva phenotype with partial rescue of the vulvaless phenotype, both to a greater degree than with wildtype MAPK1. Experiments using transiently transfected HEK293T cells indicated that the activating role of the D318G variant results at least in part from altered binding of the kinase with signaling partners, and demonstrated direct dependency of the mutant on MEK1 (MAP2K1; 176872) to drive upregulated signaling through the MPAK cascade.
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