P47811 · MK14_MOUSE
- ProteinMitogen-activated protein kinase 14
- GeneMapk14
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids360 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Phosphorylates S100A9 at 'Thr-113' (By similarity).
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]
Cofactor
Activity regulation
Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). SB203580 is an inhibitor of MAPK14.
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
212 μM | ATP (when both Thr-180 and Tyr-182 are phosphorylated) | |||||
1669 μM | ATP (when only Thr-180 is phosphorylated) | |||||
656 μM | EGFR peptide as a substrate (when both Thr-180 and Tyr-182 are phosphorylated) | |||||
2800 μM | EGFR peptide as a substrate (when only Thr-180 is phosphorylated) | |||||
2.03 μM | ATF2 as a substrate (when both Thr-180 and Tyr-182 are phosphorylated) | |||||
20.1 μM | ATF2 as a substrate (when only Thr-180 is phosphorylated) |
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameMitogen-activated protein kinase 14
- EC number
- Short namesMAP kinase 14; MAPK 14
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionP47811
- Secondary accessions
Proteomes
Organism-specific databases
Phenotypes & Variants
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 180 | Phosphorylation blocked. | ||||
Sequence: T → A | ||||||
Mutagenesis | 182 | Phosphorylation blocked. | ||||
Sequence: Y → F |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 17 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for initiator methionine, modified residue, chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Initiator methionine | 1 | Removed | ||||
Sequence: M | ||||||
Modified residue | 2 | N-acetylserine | ||||
Sequence: S | ||||||
Modified residue | 2 | Phosphoserine | ||||
Sequence: S | ||||||
Chain | PRO_0000186292 | 2-360 | Mitogen-activated protein kinase 14 | |||
Sequence: SQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGHRVAVKKLSRPFQSIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQKLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMTGYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVGTPGAELLKKISSESARNYIQSLAQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAAQALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES | ||||||
Modified residue | 16 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 53 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 152 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 180 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 180 | Phosphothreonine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysis | ||||
Sequence: T | ||||||
Modified residue | 182 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 182 | Phosphotyrosine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysis | ||||
Sequence: Y | ||||||
Modified residue | 323 | Phosphotyrosine; by ZAP70 | ||||
Sequence: Y |
Post-translational modification
Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory cytokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (By similarity).
Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3 (By similarity).
Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Macrophages, monocytes, T- and B-lymphocytes. Isoform 2 is specifically expressed in kidney and liver.
Gene expression databases
Interaction
Subunit
Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By similarity).
Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity).
This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity).
Interacts with SPAG9 and GADD45A (By similarity).
Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (By similarity).
Interacts with DUSP2; this interaction does not lead to catalytic activation of DUSP2 and dephosphrylation of MAPK14 (PubMed:16288922).
Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity).
This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity).
Interacts with SPAG9 and GADD45A (By similarity).
Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (By similarity).
Interacts with DUSP2; this interaction does not lead to catalytic activation of DUSP2 and dephosphrylation of MAPK14 (PubMed:16288922).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
XENO | P47811 | DUSP9 Q99956 | 2 | EBI-298727, EBI-3906678 | |
BINARY | P47811 | Lcp1 Q61233 | 5 | EBI-298727, EBI-309345 | |
BINARY | P47811 | Mapk11 Q9WUI1 | 10 | EBI-298727, EBI-645081 | |
BINARY | P47811 | Mapkapk2 P49138 | 2 | EBI-298727, EBI-298776 | |
XENO | P47811 | MAPKAPK2 P49137-1 | 2 | EBI-298727, EBI-15629963 | |
BINARY | P47811 | Prkn Q9WVS6 | 3 | EBI-298727, EBI-973635 | |
XENO | P47811 | PTPN7 P35236 | 2 | EBI-298727, EBI-2265723 | |
BINARY | P47811 | Slc12a2 P55012 | 2 | EBI-298727, EBI-621078 | |
BINARY | P47811 | Stk39 Q9Z1W9 | 2 | EBI-298727, EBI-444764 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 24-308 | Protein kinase | ||||
Sequence: YQNLSPVGSGAYGSVCAAFDTKTGHRVAVKKLSRPFQSIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQKLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMTGYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVGTPGAELLKKISSESARNYIQSLAQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAAQALAHAYF | ||||||
Motif | 180-182 | TXY | ||||
Sequence: TGY |
Domain
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Sequence similarities
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 4 isoforms produced by Alternative splicing.
P47811-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length360
- Mass (Da)41,287
- Last updated2007-01-23 v3
- ChecksumDFB03EBCE97BB51A
P47811-2
- Name2
- SynonymsPiccolo
P47811-3
- Name3
- Differences from canonical
- 230-254: DQLKLILRLVGTPGAELLKKISSES → NQLQQIMRLTGTPPAYLINRMPSHE
P47811-4
- Name4
- Differences from canonical
- 1-77: Missing
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A3B2WAZ7 | A0A3B2WAZ7_MOUSE | Mapk14 | 50 | ||
A0A3B2WB60 | A0A3B2WB60_MOUSE | Mapk14 | 307 | ||
B2KF34 | B2KF34_MOUSE | Mapk14 | 227 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_022359 | 1-77 | in isoform 4 | |||
Sequence: Missing | ||||||
Sequence conflict | 98 | in Ref. 7; AAF06348 | ||||
Sequence: E → G | ||||||
Sequence conflict | 107-108 | in Ref. 7; AAF06348 | ||||
Sequence: HL → LS | ||||||
Sequence conflict | 115 | in Ref. 7; AAF06348 | ||||
Sequence: N → R | ||||||
Sequence conflict | 124 | in Ref. 7; AAF06348 | ||||
Sequence: D → G | ||||||
Sequence conflict | 159-162 | in Ref. 7; AAF06348 | ||||
Sequence: NEDC → TQVI | ||||||
Sequence conflict | 166 | in Ref. 7; AAF06348 | ||||
Sequence: I → L | ||||||
Sequence conflict | 202 | in Ref. 7; AAF06348 | ||||
Sequence: Q → R | ||||||
Sequence conflict | 211-212 | in Ref. 7; AAF06348 | ||||
Sequence: CI → GF | ||||||
Sequence conflict | 224 | in Ref. 7; AAF06348 | ||||
Sequence: P → L | ||||||
Alternative sequence | VSP_007544 | 230-254 | in isoform 3 | |||
Sequence: DQLKLILRLVGTPGAELLKKISSES → NQLQQIMRLTGTPPAYLINRMPSHE | ||||||
Sequence conflict | 238 | In isoform P47811-3; in Ref. 2; BAA19741 | ||||
Sequence: L → M | ||||||
Alternative sequence | VSP_004846 | 255-278 | in isoform 2 | |||
Sequence: ARNYIQSLAQMPKMNFANVFIGAN → DAKP | ||||||
Sequence conflict | 271 | in Ref. 7; AAF06348 | ||||
Sequence: A → P | ||||||
Alternative sequence | VSP_007545 | 279-360 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 299 | in Ref. 7; AAF06348 | ||||
Sequence: A → V | ||||||
Sequence conflict | 315 | in Ref. 7; AAF06348 | ||||
Sequence: D → Y |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
U10871 EMBL· GenBank· DDBJ | AAA20888.1 EMBL· GenBank· DDBJ | mRNA | ||
D83073 EMBL· GenBank· DDBJ | BAA19741.1 EMBL· GenBank· DDBJ | mRNA | ||
AF128892 EMBL· GenBank· DDBJ | AAF34818.1 EMBL· GenBank· DDBJ | mRNA | ||
AK151348 EMBL· GenBank· DDBJ | BAE30324.1 EMBL· GenBank· DDBJ | mRNA | ||
AK153025 EMBL· GenBank· DDBJ | BAE31659.1 EMBL· GenBank· DDBJ | mRNA | ||
AK089059 EMBL· GenBank· DDBJ | BAC40726.1 EMBL· GenBank· DDBJ | mRNA | ||
AK133684 EMBL· GenBank· DDBJ | BAE21782.1 EMBL· GenBank· DDBJ | mRNA | ||
CT009661 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC012235 EMBL· GenBank· DDBJ | AAH12235.1 EMBL· GenBank· DDBJ | mRNA | ||
AF195850 EMBL· GenBank· DDBJ | AAF06348.1 EMBL· GenBank· DDBJ | mRNA | ||
X65067 EMBL· GenBank· DDBJ | CAA46200.1 EMBL· GenBank· DDBJ | mRNA |