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Mitogen-activated protein kinase 14



Rattus norvegicus (Rat)
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli


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 proinflammatory 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).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.By similarity


Mg2+By similarity

Enzyme regulationi

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 (By similarity).By similarity


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei53ATPPROSITE-ProRule annotation1
Active sitei150Proton acceptorPROSITE-ProRule annotation1


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi30 – 38ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: RGD
  • MAP kinase activity Source: RGD
  • protein C-terminus binding Source: RGD

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • intracellular signal transduction Source: UniProtKB
  • p38MAPK cascade Source: UniProtKB
  • positive regulation of myoblast differentiation Source: UniProtKB
  • positive regulation of myoblast fusion Source: UniProtKB
  • positive regulation of myotube differentiation Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: RGD
  • protein autophosphorylation Source: RGD
  • protein phosphorylation Source: RGD
  • Ras protein signal transduction Source: Reactome
  • regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • response to glucose Source: RGD
  • stress-activated MAPK cascade Source: RGD
  • transcription, DNA-templated Source: UniProtKB-KW


Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Stress response, Transcription, Transcription regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.24. 5301.
ReactomeiR-RNO-171007. p38MAPK events.

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 14 (EC:
Short name:
MAP kinase 14
Short name:
Alternative name(s):
Mitogen-activated protein kinase p38 alpha
Short name:
MAP kinase p38 alpha
Gene namesi
Synonyms:Csbp1, Csbp2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi70496. Mapk14.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: RGD
  • nucleus Source: RGD

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Chemistry databases


PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00001862942 – 360Mitogen-activated protein kinase 14Add BLAST359

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei2PhosphoserineCombined sources1
Modified residuei16PhosphothreonineBy similarity1
Modified residuei53N6-acetyllysineBy similarity1
Modified residuei152N6-acetyllysineBy similarity1
Modified residuei180PhosphothreonineCombined sources1
Modified residuei182PhosphotyrosineCombined sources1
Modified residuei323Phosphotyrosine; by ZAP70By similarity1

Post-translational modificationi

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 (By similarity). PPM1D also mediates dephosphorylation and inactivation of MAPK14 (By similarity).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).By similarity
Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases


PTM databases



Subunit structurei

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).By similarity

GO - Molecular functioni

  • protein C-terminus binding Source: RGD

Protein-protein interaction databases

IntActiP70618. 1 interactor.

Chemistry databases



3D structure databases


Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini24 – 308Protein kinasePROSITE-ProRule annotationAdd BLAST285


Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi180 – 182TXY3


The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0660. Eukaryota.

Family and domain databases

InterProiView protein in InterPro
IPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008352. MAPK_p38.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
PfamiView protein in Pfam
PF00069. Pkinase. 1 hit.
SMARTiView protein in SMART
SM00220. S_TKc. 1 hit.
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS01351. MAPK. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P70618-1) [UniParc]FASTAAdd to basket

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.

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Mass (Da):41,321
Last modified:January 23, 2007 - v3
Isoform 2 (identifier: P70618-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:

Show »
Mass (Da):41,521

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti59F → V in AAB51285 (Ref. 2) Curated1
Sequence conflicti61S → P in AAB51285 (Ref. 2) Curated1
Sequence conflicti68T → S in AAB51285 (Ref. 2) Curated1
Sequence conflicti321E → D in AAB51285 (Ref. 2) Curated1
Sequence conflicti321E → D in AAK15541 (Ref. 3) Curated1
Sequence conflicti332F → L in AAB51285 (Ref. 2) Curated1
Sequence conflicti332F → L in AAK15541 (Ref. 3) Curated1
Sequence conflicti359E → D in AAB51285 (Ref. 2) Curated1
Sequence conflicti359E → D in AAK15541 (Ref. 3) Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004847230 – 254DQLKL…ISSES → NQLQQIMRLTGTPPAYLINR MPSHE in isoform 2. 1 PublicationAdd BLAST25

Sequence databases

Select the link destinations:
Links Updated
U73142 mRNA. Translation: AAC71059.1.
U91847 mRNA. Translation: AAB51285.1.
AF346293 mRNA. Translation: AAK15541.1.

Genome annotation databases

UCSCiRGD:70496. rat. [P70618-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiMK14_RAT
AccessioniPrimary (citable) accession number: P70618
Secondary accession number(s): O08594, Q99MG4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: May 10, 2017
This is version 152 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program


Keywords - Technical termi

Complete proteome, Reference proteome


  1. SIMILARITY comments
    Index of protein domains and families