Mitogen-activated protein kinase 9 (MAPK9)
The protein contains 424 amino acids for an estimated molecular weight of 48139 Da.
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (Pub (updated: Oct. 10, 2018)
Protein identification was indicated in the following studies:
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Cellular response to cadmium ion
Cellular response to reactive oxygen species
Fc-epsilon receptor signaling pathway
Intracellular signal transduction
JNK cascade
Peptidyl-serine phosphorylation
Positive regulation of apoptotic signaling pathway
Positive regulation of gene expression
Positive regulation of macrophage derived foam cell differentiation
Positive regulation of podosome assembly
Positive regulation of protein ubiquitination
Positive regulation of transcription factor catabolic process
Protein localization to tricellular tight junction
Protein phosphorylation
Regulation of circadian rhythm
Regulation of DNA-binding transcription factor activity
Regulation of gene expression
Rhythmic process
The reference OMIM entry for this protein is 602896
Mitogen-activated protein kinase 9; mapk9
Protein kinase, mitogen-activated, 9; prkm9
C-jun kinase 2; jnk2
CLONING
The transcriptional activity of the c-Jun protooncoprotein (see 165160) is augmented through phosphorylation at 2 sites by c-Jun amino-terminal kinases (JNKs). Using in-gel kinase assays, Hibi et al. (1993) identified 2 JNKs, 46 and 55 kD in size. The 46-kD protein JNK1 (601158) was shown to be a member of the mitogen-activated protein kinase (MAPK) family. Using a JNK1 cDNA as a probe, Kallunki et al. (1994) and Sluss et al. (1994) isolated cDNAs encoding the 55-kD protein, which both designated JNK2. Kallunki et al. (1994) reported that the sequence of the predicted 424-amino acid JNK2 protein is 83% identical to that of JNK1. Both JNKs contain a thr-pro-tyr phosphorylation motif. Northern blot analysis revealed that JNK2 is expressed as multiple transcripts in many cell types. By analysis of brain cDNAs, Gupta et al. (1996) identified 10 JNK isoforms, 4 of which are produced by alternative splicing of JNK2. Isoforms of 46 and 55 kD are encoded by both the JNK1 and JNK2 genes. The JNK isoforms differ in their interactions with transcription factors ATF2 (CREB2; 123811), ELK1 (311040), and Jun.GENE FUNCTION
Kallunki et al. (1994) showed that expression of JNK2 in mammalian cells potentiated activation of a c-Jun-responsive promoter, while expression of JNK1 had no effect. Using in vitro binding assays, they found that JNK2 bound c-Jun approximately 25 times more efficiently than did JNK1. The authors traced this difference to a small beta-strand-like region near the catalytic pocket of the enzyme. Sluss et al. (1994) demonstrated that both UV radiation and the proinflammatory cytokine TNF-alpha (191160) induce JNK1 and JNK2. Direct association of p53 (191170) with the cellular protein MDM2 (164785) results in ubiquitination and subsequent degradation of p53. Based on evidence for JNK association with p53, Fuchs et al. (1998) sought to elucidate the role of nonactive JNK2 in regulating p53 stability. The amount of p53-JNK complex was inversely correlated with the p53 level. A peptide corresponding to the JNK binding site on p53 efficiently blocked ubiquitination of p53. Similarly, p53 lacking the JNK binding site exhibited a longer half-life than wildtype p53. Outcompeting JNK association with p53 increased the level of p53, whereas overexpression of a phosphorylation mutant form of JNK inhibited p53 accumulation. JNK-p53 and MDM2-p53 complexes were preferentially found in G0/G1 and S/G2M phases of the cell cycle, respectively. Altogether, these data indicated that JNK is an MDM2-independent regulator of p53 stability in nonstressed cells. Gao et al. (2004) found that in the case of c-JUN (165160) and JUNB (165161), extracellular stimuli modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) cascade after T cell stimulation accelerated degradation of c-JUN and JUNB through phosphorylation-dependent activation of the E3 ligase ITCH (606409). Gao et al. (2004) found that this pathway modulates cytokine production by effector T cells. Cell stress is accompanied by downregulated rRNA synthesis. Mayer et al. (2005) found that stress-dependent inhibition of RNA polymerase I (Pol I; see 602000) was mediated by inactivation of the Pol I-specific transcription factor TIFIA (RRN3; 605121) in mammalian cells. Inactivation was due to JNK2 phosphorylation of TIFIA at residue thr200, w ... More on the omim web site
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 602896 was added.
Feb. 23, 2019: Protein entry updated
Automatic update: comparative model was added.
Feb. 23, 2019: Protein entry updated
Automatic update: model status changed
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).