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P70618

- MK14_RAT

UniProt

P70618 - MK14_RAT

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Protein
Mitogen-activated protein kinase 14
Gene
Mapk14, Csbp1, Csbp2
Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at transcript leveli

Functioni

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 activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Magnesium 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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei53 – 531ATP By similarity
Active sitei150 – 1501Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi30 – 389ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: RGD
  2. MAP kinase activity Source: UniProtKB
  3. protein C-terminus binding Source: RGD
  4. protein binding Source: RGD
Complete GO annotation...

GO - Biological processi

  1. apoptotic process Source: UniProtKB-KW
  2. intracellular signal transduction Source: UniProtKB
  3. p38MAPK cascade Source: UniProtKB
  4. positive regulation of myoblast differentiation Source: UniProtKB
  5. positive regulation of myoblast fusion Source: UniProtKB
  6. positive regulation of myotube differentiation Source: UniProtKB
  7. protein autophosphorylation Source: RGD
  8. protein phosphorylation Source: RGD
  9. regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  10. response to glucose Source: RGD
  11. stress-activated MAPK cascade Source: RGD
  12. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis, Stress response, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 14 (EC:2.7.11.24)
Short name:
MAP kinase 14
Short name:
MAPK 14
Alternative name(s):
CRK1
Mitogen-activated protein kinase p38 alpha
Short name:
MAP kinase p38 alpha
Gene namesi
Name:Mapk14
Synonyms:Csbp1, Csbp2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Unplaced

Organism-specific databases

RGDi70496. Mapk14.

Subcellular locationi

Cytoplasm By similarity. Nucleus By similarity

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. cytosol Source: RGD
  3. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed By similarity
Chaini2 – 360359Mitogen-activated protein kinase 14
PRO_0000186294Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserine By similarity
Modified residuei2 – 21Phosphoserine By similarity
Modified residuei16 – 161Phosphothreonine By similarity
Modified residuei53 – 531N6-acetyllysine By similarity
Modified residuei152 – 1521N6-acetyllysine By similarity
Modified residuei180 – 1801Phosphothreonine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysis By similarity
Modified residuei182 – 1821Phosphotyrosine; by MAP2K3, MAP2K4, MAP2K6 and autocatalysis By similarity
Modified residuei323 – 3231Phosphotyrosine; by ZAP70 By similarity

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.
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 - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiP70618.

PTM databases

PhosphoSiteiP70618.

Expressioni

Gene expression databases

GenevestigatoriP70618.

Interactioni

Subunit structurei

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.

Protein-protein interaction databases

DIPiDIP-29878N.
IntActiP70618. 1 interaction.
MINTiMINT-4777441.

Structurei

3D structure databases

ProteinModelPortaliP70618.
SMRiP70618. Positions 4-354.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini24 – 308285Protein kinase
Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi180 – 1823TXY

Domaini

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

Sequence similaritiesi

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
PhylomeDBiP70618.

Family and domain databases

InterProiIPR011009. 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]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSiPR01773. P38MAPKINASE.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

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. Align

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.

« Hide

MSQERPTFYR QELNKTVWEV PERYQNLSPV GSGAYGSVCA AFDTKTGHRV    50
AVKKLSRPFQ SIIHAKRTYR ELRLLKHMKH ENVIGLLDVF TPARSLEEFN 100
DVYLVTHLMG ADLNNIVKCQ KLTDDHVQFL IYQILRGLKY IHSADIIHRD 150
LKPSNLAVNE DCELKILDFG LARHTDDEMT GYVATRWYRA PEIMLNWMHY 200
NQTVDIWSVG CIMAELLTGR TLFPGTDHID QLKLILRLVG TPGAELLKKI 250
SSESARNYIQ SLAQMPKMNF ANVFIGANPL AVDLLEKMLV LDSDKRITAA 300
QALAHAYFAQ YHDPDDEPVA EPYDQSFESR DFLIDEWKSL TYDEVISFVP 350
PPLDQEEMES 360
Length:360
Mass (Da):41,321
Last modified:January 23, 2007 - v3
Checksum:i59FBF1FC3398C5CA
GO
Isoform 2 (identifier: P70618-2) [UniParc]FASTAAdd to Basket

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

Show »
Length:360
Mass (Da):41,521
Checksum:i77B9CC122D86E06D
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei230 – 25425DQLKL…ISSES → NQLQQIMRLTGTPPAYLINR MPSHE in isoform 2.
VSP_004847Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti59 – 591F → V in AAB51285. 1 Publication
Sequence conflicti61 – 611S → P in AAB51285. 1 Publication
Sequence conflicti68 – 681T → S in AAB51285. 1 Publication
Sequence conflicti321 – 3211E → D in AAB51285. 1 Publication
Sequence conflicti321 – 3211E → D in AAK15541. 1 Publication
Sequence conflicti332 – 3321F → L in AAB51285. 1 Publication
Sequence conflicti332 – 3321F → L in AAK15541. 1 Publication
Sequence conflicti359 – 3591E → D in AAB51285. 1 Publication
Sequence conflicti359 – 3591E → D in AAK15541. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U73142 mRNA. Translation: AAC71059.1.
U91847 mRNA. Translation: AAB51285.1.
AF346293 mRNA. Translation: AAK15541.1.
UniGeneiRn.88085.

Genome annotation databases

UCSCiRGD:70496. rat. [P70618-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U73142 mRNA. Translation: AAC71059.1 .
U91847 mRNA. Translation: AAB51285.1 .
AF346293 mRNA. Translation: AAK15541.1 .
UniGenei Rn.88085.

3D structure databases

ProteinModelPortali P70618.
SMRi P70618. Positions 4-354.
ModBasei Search...

Protein-protein interaction databases

DIPi DIP-29878N.
IntActi P70618. 1 interaction.
MINTi MINT-4777441.

Chemistry

BindingDBi P70618.
ChEMBLi CHEMBL4825.

PTM databases

PhosphoSitei P70618.

Proteomic databases

PRIDEi P70618.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

UCSCi RGD:70496. rat. [P70618-1 ]

Organism-specific databases

RGDi 70496. Mapk14.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000233024.
HOVERGENi HBG014652.
PhylomeDBi P70618.

Gene expression databases

Genevestigatori P70618.

Family and domain databases

InterProi IPR011009. 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 ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
PRINTSi PR01773. P38MAPKINASE.
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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.

Entry informationi

Entry nameiMK14_RAT
AccessioniPrimary (citable) accession number: P70618
Secondary accession number(s): O08594, Q99MG4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: September 3, 2014
This is version 131 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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