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P70618 (MK14_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase 14

Short name=MAP kinase 14
Short name=MAPK 14
EC=2.7.11.24
Alternative name(s):
CRK1
Mitogen-activated protein kinase p38 alpha
Short name=MAP kinase p38 alpha
Gene names
Name:Mapk14
Synonyms:Csbp1, Csbp2
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length360 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at transcript level

General annotation (Comments)

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 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.

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme 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 By similarity.

Subunit structure

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, CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1 By similarity. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B By similarity.

Subcellular location

Cytoplasm By similarity. Nucleus By similarity.

Domain

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

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 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.

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Stress response
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular signal transduction

Inferred from sequence or structural similarity PubMed 7914033. Source: UniProtKB

p38MAPK cascade

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of myoblast differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of myoblast fusion

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of myotube differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

protein autophosphorylation

Inferred from direct assay PubMed 16407200. Source: RGD

protein phosphorylation

Inferred from direct assay PubMed 16407200PubMed 16879317PubMed 21607062. Source: RGD

regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

response to glucose

Inferred from expression pattern PubMed 18579738. Source: RGD

stress-activated MAPK cascade

Inferred from direct assay PubMed 16407200. Source: RGD

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity PubMed 10601328. Source: UniProtKB

cytosol

Inferred from direct assay PubMed 16407200PubMed 9779826. Source: RGD

nucleus

Inferred from sequence or structural similarity PubMed 10601328. Source: UniProtKB

   Molecular_functionATP binding

Inferred from direct assay PubMed 16879317. Source: RGD

MAP kinase activity

Inferred from sequence or structural similarity PubMed 7914033. Source: UniProtKB

protein C-terminus binding

Inferred from direct assay PubMed 16407200. Source: RGD

protein binding

Inferred from physical interaction PubMed 21607062. Source: RGD

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P70618-1)

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.
Isoform 2 (identifier: P70618-2)

The sequence of this isoform differs from the canonical sequence as follows:
     230-254: DQLKLILRLVGTPGAELLKKISSES → NQLQQIMRLTGTPPAYLINRMPSHE

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 360359Mitogen-activated protein kinase 14
PRO_0000186294

Regions

Domain24 – 308285Protein kinase
Nucleotide binding30 – 389ATP By similarity
Motif180 – 1823TXY

Sites

Active site1501Proton acceptor By similarity
Binding site531ATP By similarity

Amino acid modifications

Modified residue21N-acetylserine By similarity
Modified residue21Phosphoserine By similarity
Modified residue161Phosphothreonine By similarity
Modified residue531N6-acetyllysine By similarity
Modified residue1521N6-acetyllysine By similarity
Modified residue1801Phosphothreonine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysis By similarity
Modified residue1821Phosphotyrosine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysis By similarity
Modified residue3231Phosphotyrosine; by ZAP70 By similarity

Natural variations

Alternative sequence230 – 25425DQLKL…ISSES → NQLQQIMRLTGTPPAYLINR MPSHE in isoform 2.
VSP_004847

Experimental info

Sequence conflict591F → V in AAB51285. Ref.2
Sequence conflict611S → P in AAB51285. Ref.2
Sequence conflict681T → S in AAB51285. Ref.2
Sequence conflict3211E → D in AAB51285. Ref.2
Sequence conflict3211E → D in AAK15541. Ref.3
Sequence conflict3321F → L in AAB51285. Ref.2
Sequence conflict3321F → L in AAK15541. Ref.3
Sequence conflict3591E → D in AAB51285. Ref.2
Sequence conflict3591E → D in AAK15541. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 59FBF1FC3398C5CA

FASTA36041,321
        10         20         30         40         50         60 
MSQERPTFYR QELNKTVWEV PERYQNLSPV GSGAYGSVCA AFDTKTGHRV AVKKLSRPFQ 

        70         80         90        100        110        120 
SIIHAKRTYR ELRLLKHMKH ENVIGLLDVF TPARSLEEFN DVYLVTHLMG ADLNNIVKCQ 

       130        140        150        160        170        180 
KLTDDHVQFL IYQILRGLKY IHSADIIHRD LKPSNLAVNE DCELKILDFG LARHTDDEMT 

       190        200        210        220        230        240 
GYVATRWYRA PEIMLNWMHY NQTVDIWSVG CIMAELLTGR TLFPGTDHID QLKLILRLVG 

       250        260        270        280        290        300 
TPGAELLKKI SSESARNYIQ SLAQMPKMNF ANVFIGANPL AVDLLEKMLV LDSDKRITAA 

       310        320        330        340        350        360 
QALAHAYFAQ YHDPDDEPVA EPYDQSFESR DFLIDEWKSL TYDEVISFVP PPLDQEEMES 

« Hide

Isoform 2 [UniParc].

Checksum: 77B9CC122D86E06D
Show »

FASTA36041,521

References

[1]"Suppression subtractive hybridization (SSH) identifies prolactin stimulation of p38 MAP kinase gene expression in Nb2 T lymphoma cells: molecular cloning of rat p38 MAP kinase."
Nemeth E., Bole-Feysot C., Tashima L.S.
J. Mol. Endocrinol. 20:151-156(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]Garcia G.E., Han J., Feng L.
Submitted (APR-1997) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Strain: Lewis.
Tissue: Kidney.
[3]Reick M.E., Goldsmith E.J.
Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[4]"In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance."
Shi Y., Gaestel M.
Biol. Chem. 383:1519-1536(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[5]"Mechanisms and functions of p38 MAPK signalling."
Cuadrado A., Nebreda A.R.
Biochem. J. 429:403-417(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U73142 mRNA. Translation: AAC71059.1.
U91847 mRNA. Translation: AAB51285.1.
AF346293 mRNA. Translation: AAK15541.1.
UniGeneRn.88085.

3D structure databases

ProteinModelPortalP70618.
SMRP70618. Positions 4-354.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-29878N.
IntActP70618. 1 interaction.
MINTMINT-4777441.

Chemistry

BindingDBP70618.
ChEMBLCHEMBL4825.

PTM databases

PhosphoSiteP70618.

Proteomic databases

PRIDEP70618.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

UCSCRGD:70496. rat. [P70618-1]

Organism-specific databases

RGD70496. Mapk14.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233024.
HOVERGENHBG014652.
PhylomeDBP70618.

Enzyme and pathway databases

ReactomeREACT_212996. Signal Transduction.

Gene expression databases

GenevestigatorP70618.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008352. MAPK_p38.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSPR01773. P38MAPKINASE.
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetSearch...

Entry information

Entry nameMK14_RAT
AccessionPrimary (citable) accession number: P70618
Secondary accession number(s): O08594, Q99MG4
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: June 11, 2014
This is version 130 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families