UniProtKB - P70618 (MK14_RAT)
Mitogen-activated protein kinase 14
Mapk14
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).
By similarityCatalytic activityi
Cofactori
Activity regulationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 53 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 150 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 30 – 38 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: RGD
- enzyme binding Source: RGD
- kinase activity Source: RGD
- MAP kinase activity Source: RGD
- mitogen-activated protein kinase p38 binding Source: RGD
- NFAT protein binding Source: RGD
- protein C-terminus binding Source: RGD
- protein kinase activity Source: RGD
- protein phosphatase binding Source: RGD
- protein serine/threonine/tyrosine kinase activity Source: RHEA
- protein serine/threonine kinase activity Source: RGD
- protein serine kinase activity Source: RHEA
GO - Biological processi
- angiogenesis Source: RGD
- apoptotic process Source: UniProtKB-KW
- bone development Source: RGD
- cartilage condensation Source: RGD
- cell morphogenesis Source: RGD
- cellular response to DNA damage stimulus Source: RGD
- cellular response to ionizing radiation Source: RGD
- cellular response to lipopolysaccharide Source: RGD
- cellular response to lipoteichoic acid Source: RGD
- cellular response to tumor necrosis factor Source: RGD
- cellular response to vascular endothelial growth factor stimulus Source: RGD
- cellular response to virus Source: RGD
- chondrocyte differentiation Source: RGD
- DNA damage checkpoint signaling Source: RGD
- fatty acid oxidation Source: RGD
- glucose metabolic process Source: RGD
- intracellular signal transduction Source: UniProtKB
- lipopolysaccharide-mediated signaling pathway Source: RGD
- MAPK cascade Source: RGD
- negative regulation of canonical Wnt signaling pathway Source: RGD
- negative regulation of hippo signaling Source: RGD
- osteoblast differentiation Source: RGD
- osteoclast differentiation Source: RGD
- p38MAPK cascade Source: UniProtKB
- peptidyl-serine phosphorylation Source: RGD
- placenta development Source: RGD
- positive regulation of brown fat cell differentiation Source: RGD
- positive regulation of cardiac muscle cell proliferation Source: RGD
- positive regulation of cyclase activity Source: RGD
- positive regulation of erythrocyte differentiation Source: RGD
- positive regulation of gene expression Source: RGD
- positive regulation of glucose import Source: RGD
- positive regulation of interleukin-12 production Source: RGD
- positive regulation of myoblast differentiation Source: UniProtKB
- positive regulation of myoblast fusion Source: UniProtKB
- positive regulation of myotube differentiation Source: UniProtKB
- positive regulation of protein import into nucleus Source: RGD
- positive regulation of reactive oxygen species metabolic process Source: RGD
- positive regulation of transcription by RNA polymerase II Source: RGD
- protein autophosphorylation Source: RGD
- protein phosphorylation Source: RGD
- regulation of cytokine production involved in inflammatory response Source: RGD
- regulation of ossification Source: RGD
- regulation of synaptic membrane adhesion Source: RGD
- regulation of transcription, DNA-templated Source: RGD
- regulation of transcription by RNA polymerase II Source: UniProtKB
- response to dietary excess Source: RGD
- response to glucose Source: RGD
- response to insulin Source: RGD
- response to lipopolysaccharide Source: RGD
- response to muramyl dipeptide Source: RGD
- response to muscle stretch Source: RGD
- signal transduction in response to DNA damage Source: RGD
- skeletal muscle tissue development Source: RGD
- stress-activated MAPK cascade Source: RGD
- stress-induced premature senescence Source: RGD
- striated muscle cell differentiation Source: RGD
- transmembrane receptor protein serine/threonine kinase signaling pathway Source: RGD
- vascular endothelial growth factor receptor signaling pathway Source: RGD
Keywordsi
Molecular function | Kinase, Serine/threonine-protein kinase, Transferase |
Biological process | Apoptosis, Stress response, Transcription, Transcription regulation |
Ligand | ATP-binding, Nucleotide-binding |
Enzyme and pathway databases
BRENDAi | 2.7.11.24, 5301 |
Reactomei | R-RNO-168638, NOD1/2 Signaling Pathway R-RNO-171007, p38MAPK events R-RNO-198753, ERK/MAPK targets R-RNO-2559580, Oxidative Stress Induced Senescence R-RNO-376172, DSCAM interactions R-RNO-418592, ADP signalling through P2Y purinoceptor 1 R-RNO-432142, Platelet sensitization by LDL R-RNO-4420097, VEGFA-VEGFR2 Pathway R-RNO-450302, activated TAK1 mediates p38 MAPK activation R-RNO-450341, Activation of the AP-1 family of transcription factors R-RNO-525793, Myogenesis R-RNO-5668599, RHO GTPases Activate NADPH Oxidases R-RNO-6798695, Neutrophil degranulation R-RNO-6804756, Regulation of TP53 Activity through Phosphorylation |
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 |
Organismi | Rattus norvegicus (Rat) |
Taxonomic identifieri | 10116 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Rattus |
Proteomesi |
|
Organism-specific databases
RGDi | 70496, Mapk14 |
Subcellular locationi
Cytoskeleton
- spindle pole Source: RGD
Cytosol
- cytosol Source: RGD
Mitochondrion
- mitochondrion Source: RGD
Nucleus
- nucleus Source: RGD
Other locations
- cytoplasm Source: UniProtKB
- glutamatergic synapse Source: RGD
Keywords - Cellular componenti
Cytoplasm, NucleusPTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Initiator methioninei | RemovedBy similarity | |||
ChainiPRO_0000186294 | 2 – 360 | Mitogen-activated protein kinase 14Add BLAST | 359 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 2 | N-acetylserineBy similarity | 1 | |
Modified residuei | 2 | PhosphoserineCombined sources | 1 | |
Modified residuei | 16 | PhosphothreonineBy similarity | 1 | |
Modified residuei | 53 | N6-acetyllysineBy similarity | 1 | |
Modified residuei | 152 | N6-acetyllysineBy similarity | 1 | |
Modified residuei | 180 | PhosphothreonineCombined sources | 1 | |
Modified residuei | 182 | PhosphotyrosineCombined sources | 1 | |
Modified residuei | 323 | Phosphotyrosine; by ZAP70By similarity | 1 |
Post-translational modificationi
Keywords - PTMi
Acetylation, Phosphoprotein, Ubl conjugationProteomic databases
jPOSTi | P70618 |
PaxDbi | P70618 |
PRIDEi | P70618 |
PTM databases
iPTMneti | P70618 |
PhosphoSitePlusi | P70618 |
Interactioni
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 similarityGO - Molecular functioni
- enzyme binding Source: RGD
- mitogen-activated protein kinase p38 binding Source: RGD
- NFAT protein binding Source: RGD
- protein C-terminus binding Source: RGD
- protein phosphatase binding Source: RGD
Protein-protein interaction databases
DIPi | DIP-29878N |
IntActi | P70618, 2 interactors |
MINTi | P70618 |
STRINGi | 10116.ENSRNOP00000000617 |
Chemistry databases
BindingDBi | P70618 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 24 – 308 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 285 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 180 – 182 | TXY | 3 |
Domaini
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG0660, Eukaryota |
InParanoidi | P70618 |
PhylomeDBi | P70618 |
Family and domain databases
CDDi | cd07877, STKc_p38alpha, 1 hit |
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR003527, MAP_kinase_CS IPR008352, MAPK_p38-like IPR038784, p38alpha IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
PRINTSi | PR01773, P38MAPKINASE |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS01351, MAPK, 1 hit PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MSQERPTFYR QELNKTVWEV PERYQNLSPV GSGAYGSVCA AFDTKTGHRV
60 70 80 90 100
AVKKLSRPFQ SIIHAKRTYR ELRLLKHMKH ENVIGLLDVF TPARSLEEFN
110 120 130 140 150
DVYLVTHLMG ADLNNIVKCQ KLTDDHVQFL IYQILRGLKY IHSADIIHRD
160 170 180 190 200
LKPSNLAVNE DCELKILDFG LARHTDDEMT GYVATRWYRA PEIMLNWMHY
210 220 230 240 250
NQTVDIWSVG CIMAELLTGR TLFPGTDHID QLKLILRLVG TPGAELLKKI
260 270 280 290 300
SSESARNYIQ SLAQMPKMNF ANVFIGANPL AVDLLEKMLV LDSDKRITAA
310 320 330 340 350
QALAHAYFAQ YHDPDDEPVA EPYDQSFESR DFLIDEWKSL TYDEVISFVP
360
PPLDQEEMES
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketQ56A33 | Q56A33_RAT | Mitogen-activated protein kinase 14 | Mapk14 rCG_61074 | 360 | Annotation score: | ||
G3V617 | G3V617_RAT | Mitogen-activated protein kinase 14 | Mapk14 rCG_61074 | 360 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 59 | F → V in AAB51285 (Ref. 2) Curated | 1 | |
Sequence conflicti | 61 | S → P in AAB51285 (Ref. 2) Curated | 1 | |
Sequence conflicti | 68 | T → S in AAB51285 (Ref. 2) Curated | 1 | |
Sequence conflicti | 321 | E → D in AAB51285 (Ref. 2) Curated | 1 | |
Sequence conflicti | 321 | E → D in AAK15541 (Ref. 3) Curated | 1 | |
Sequence conflicti | 332 | F → L in AAB51285 (Ref. 2) Curated | 1 | |
Sequence conflicti | 332 | F → L in AAK15541 (Ref. 3) Curated | 1 | |
Sequence conflicti | 359 | E → D in AAB51285 (Ref. 2) Curated | 1 | |
Sequence conflicti | 359 | E → D in AAK15541 (Ref. 3) Curated | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_004847 | 230 – 254 | DQLKL…ISSES → NQLQQIMRLTGTPPAYLINR MPSHE in isoform 2. 1 PublicationAdd BLAST | 25 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U73142 mRNA Translation: AAC71059.1 U91847 mRNA Translation: AAB51285.1 AF346293 mRNA Translation: AAK15541.1 |
Genome annotation databases
UCSCi | RGD:70496, rat [P70618-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U73142 mRNA Translation: AAC71059.1 U91847 mRNA Translation: AAB51285.1 AF346293 mRNA Translation: AAK15541.1 |
3D structure databases
BMRBi | P70618 |
SMRi | P70618 |
ModBasei | Search... |
Protein-protein interaction databases
DIPi | DIP-29878N |
IntActi | P70618, 2 interactors |
MINTi | P70618 |
STRINGi | 10116.ENSRNOP00000000617 |
Chemistry databases
BindingDBi | P70618 |
ChEMBLi | CHEMBL4825 |
PTM databases
iPTMneti | P70618 |
PhosphoSitePlusi | P70618 |
Proteomic databases
jPOSTi | P70618 |
PaxDbi | P70618 |
PRIDEi | P70618 |
Genome annotation databases
UCSCi | RGD:70496, rat [P70618-1] |
Organism-specific databases
RGDi | 70496, Mapk14 |
Phylogenomic databases
eggNOGi | KOG0660, Eukaryota |
InParanoidi | P70618 |
PhylomeDBi | P70618 |
Enzyme and pathway databases
BRENDAi | 2.7.11.24, 5301 |
Reactomei | R-RNO-168638, NOD1/2 Signaling Pathway R-RNO-171007, p38MAPK events R-RNO-198753, ERK/MAPK targets R-RNO-2559580, Oxidative Stress Induced Senescence R-RNO-376172, DSCAM interactions R-RNO-418592, ADP signalling through P2Y purinoceptor 1 R-RNO-432142, Platelet sensitization by LDL R-RNO-4420097, VEGFA-VEGFR2 Pathway R-RNO-450302, activated TAK1 mediates p38 MAPK activation R-RNO-450341, Activation of the AP-1 family of transcription factors R-RNO-525793, Myogenesis R-RNO-5668599, RHO GTPases Activate NADPH Oxidases R-RNO-6798695, Neutrophil degranulation R-RNO-6804756, Regulation of TP53 Activity through Phosphorylation |
Miscellaneous databases
PROi | PR:P70618 |
Family and domain databases
CDDi | cd07877, STKc_p38alpha, 1 hit |
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR003527, MAP_kinase_CS IPR008352, MAPK_p38-like IPR038784, p38alpha IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
PRINTSi | PR01773, P38MAPKINASE |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS01351, MAPK, 1 hit PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | MK14_RAT | |
Accessioni | P70618Primary (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: | February 23, 2022 | |
This is version 177 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- SIMILARITY comments
Index of protein domains and families