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MAPK14 - mitogen-activated protein kinase 14 (human)

Gene
Symbol
Dates
  • Create:
    2016-09-14
  • Modify:
    2025-01-29
Description
The protein encoded by the MAPK14 gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
Enables MAP kinase activity; mitogen-activated protein kinase p38 binding activity; and protein phosphatase binding activity. Involved in several processes, including cellular response to radiation; intracellular signal transduction; and regulation of cytokine production. Acts upstream of or within cellular response to lipopolysaccharide. Located in nuclear speck. Is active in cytosol. Implicated in colon cancer; colorectal carcinoma; nasopharynx carcinoma; and rectum cancer. Biomarker of gastric adenocarcinoma.

1 Names and Identifiers

1.1 Synonyms

  • CSBP
  • CSBP1
  • CSBP2
  • CSPB1
  • EXIP
  • Mxi2
  • PRKM14
  • PRKM15
  • RK
  • SAPK2A
  • p38
  • p38ALPHA
  • CSAID-binding protein
  • MAP kinase 14
  • MAP kinase Mxi2
  • MAP kinase p38 alpha
  • MAX-interacting protein 2
  • cytokine suppressive anti-inflammatory drug binding protein
  • mitogen-activated protein kinase p38 alpha
  • p38 MAP kinase
  • p38 mitogen activated protein kinase
  • p38alpha Exip
  • stress-activated protein kinase 2A

1.1.1 MeSH Entry Terms

  • CSAID-Binding Protein
  • Cytokine Suppressive Anti-inflammatory Drug Binding Protein
  • Kinase CSBP
  • MAPK14 Mitogen-Activated Protein Kinase
  • MAPK14
  • MAX-Interacting Protein 2
  • Mxi2 Protein
  • SAPK2a
  • Stress-activated protein kinase 2a
  • p38alpha Mitogen-Activated Protein Kinase
  • p38alpha MAP Kinase
  • p38alphaMAPK

1.2 Other Identifiers

1.2.1 HGNC ID

1.2.2 Ensembl ID

1.2.3 Alliance Gene ID

1.2.4 Bgee Gene ID

1.2.5 Enzyme Commission (EC) Number

1.2.6 MIM Number

1.2.7 NCI Thesaurus Code

1.2.8 Open Targets ID

1.2.9 PharmGKB ID

1.2.10 Pharos Target

1.2.11 VEuPathDB ID

1.2.12 Wikidata

3 Proteins

3.1 Protein 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 (PMID: 9687510, PMID: 9792677). 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 (PMID: 9687510, PMID: 9792677). 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 (PMID: 11154262). MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53 (PMID: 10747897). 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 (PMID: 17003045). MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9 (PMID: 19893488). 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 (PMID: 16932740). 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 (PMID: 20188673). 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 (PMID: 10330143, PMID: 9430721, PMID: 9858528). 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 (PMID: 11333986). Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation (PMID: 20932473). 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 (PMID: 10943842). Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113' (PMID: 15905572). Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis (PMID: 35857590).

(Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minutes and is inhibited by kinase-specific inhibitors SB203580 and siRNA (PMID: 21586573).

3.2 Protein Isoforms

Isoform
Isoform CSBP2
UniProt ID
RefSeq Accession
Isoform
Isoform CSBP1
UniProt ID
RefSeq Accession
Isoform
Isoform Mxi2
UniProt ID
RefSeq Accession
Isoform
Isoform Exip
UniProt ID
RefSeq Accession
Isoform
Isoform 5
UniProt ID
RefSeq Accession

3.3 Protein 3D Structures

3.3.1 PDB Structures

3.3.2 NCBI Protein Structures

3.3.3 AlphaFold Structures

Highly accurate protein structure prediction with AlphaFold. Nature. 2021 Aug;596(7873):583-589. DOI:10.1038/s41586-021-03819-2. PMID:34265844; PMCID:PMC8371605

3.4 Protein Targets

4 Chemicals and Bioactivities

4.1 Tested Compounds

5 BioAssays

5.1 Small-Molecule BioAssays

5.2 RNAi BioAssays

6 Diseases and Phenotypes

6.1 Gene-Disease Associations

7 Interactions and Pathways

7.1 Chemical-Gene Interactions

7.2 Interactions

7.3 Pathways

8 Biochemical Reactions

9 Expression

10 Target Development Level

11 Literature

11.1 Consolidated References

11.2 NLM Curated PubMed Citations

11.3 Gene-Chemical Co-Occurrences in Literature

11.4 Gene-Gene Co-Occurrences in Literature

11.5 Gene-Disease Co-Occurrences in Literature

12 Patents

12.1 Gene-Chemical Co-Occurrences in Patents

12.2 Gene-Gene Co-Occurrences in Patents

12.3 Gene-Disease Co-Occurrences in Patents

13 Classification

13.1 Gene Family

13.2 MeSH Tree

13.3 NCI Thesaurus Tree

13.4 Gene Ontology: Biological Process

13.5 Gene Ontology: Cellular Component

13.6 Gene Ontology: Molecular Function

13.7 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

13.8 ChEMBL Target Tree

13.9 Enzyme Classification

14 Information Sources

  1. NCBI Gene
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    https://www.ncbi.nlm.nih.gov/home/about/policies/
  2. PubChem
  3. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
    Mitogen-Activated Protein Kinase 14
    https://meshb.nlm.nih.gov/record/ui?ui=D048308
  4. Alliance of Genome Resources
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    https://www.alliancegenome.org/privacy-warranty-licensing
  5. BindingDB
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    https://www.bindingdb.org/rwd/bind/info.jsp
  6. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  7. Chemical Probes Portal
  8. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  9. Drug Gene Interaction database (DGIdb)
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    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  10. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  11. IUPHAR/BPS Guide to PHARMACOLOGY
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    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  12. Therapeutic Target Database (TTD)
  13. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  14. BioGRID
    LICENSE
    The MIT License (MIT); Copyright Mike Tyers Lab
    https://wiki.thebiogrid.org/doku.php/terms_and_conditions
  15. Database of Interacting Proteins (DIP)
    LICENSE
    All DIP database records available under the terms set by the Creative Commons Attribution-NoDerivs License.
    https://dip.doe-mbi.ucla.edu/dip/termsofuse.html
  16. STRING: functional protein association networks
  17. Open Targets
    LICENSE
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    https://platform-docs.opentargets.org/licence
  18. HUGO Gene Nomenclature Committee (HGNC)
    LICENSE
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    https://www.genenames.org/about/
  19. NCBI Gene Expression Omnibus (GEO)
  20. NCBI Structure
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    https://www.ncbi.nlm.nih.gov/home/about/policies/
  21. NCI Thesaurus (NCIt)
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    https://www.cancer.gov/policies/copyright-reuse
  22. Online Mendelian Inheritance in Man (OMIM)
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    https://omim.org/help/copyright
  23. PharmGKB
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    https://www.pharmgkb.org/page/policies
  24. Pharos
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    https://pharos.nih.gov/about
  25. RCSB Protein Data Bank (RCSB PDB)
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    https://www.rcsb.org/pages/policies
  26. Swiss Institute of Bioinformatics Bgee
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    Creative Commons Zero license (CC0)
    https://www.bgee.org/about/
  27. UniProt
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    https://www.uniprot.org/help/license
  28. VEuPathDB: The Eukaryotic Pathogen, Vector and Host Informatics Resource
    LICENSE
    All data on VEuPathDB websites are provided freely for public use.
    https://veupathdb.org/veupathdb/app/static-content/about.html
  29. Wikidata
  30. Swiss Institute of Bioinformatics ENZYME
    LICENSE
    Copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution (CC BY 4.0) License (https://creativecommons.org/licenses/by/4.0/).
    https://enzyme.expasy.org/enzyme.get
    Enzyme Classification
    https://enzyme.expasy.org/
  31. Gene Ontology (GO)
    LICENSE
    Gene Ontology Consortium data and data products are licensed under the Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/legalcode)
    http://geneontology.org/docs/go-citation-policy/
  32. AlphaFold DB
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    All of the data provided is freely available for both academic and commercial use under Creative Commons Attribution 4.0 (CC-BY 4.0) licence terms.
    https://alphafold.ebi.ac.uk/faq
  33. Rhea - annotated reactions database
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    https://www.rhea-db.org/help/license-disclaimer
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