Tchem MAPK14 Mitogen-activated protein kinase 14

Protein Summary

Description

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. 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'. (Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minute and is inhibited by kinase-specific inhibitors SB203580 and siRNA (PubMed:21586573). The protein encoded by this 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]

Uniprot Accession IDs

• Q16539
• A6ZJ92
• A8K6P4
• B0LPH0
• B5TY32
• O60776
• Q13083
• Q14084
• Q8TDX0
• MAP kinase 14

Gene Name

• MAPK14

Ensembl ID

• ENST00000229794
• ENSP00000229794
• ENSG00000112062
• ENST00000229795
• ENSP00000229795
• ENST00000310795
• ENSP00000308669

Symbol

• CSBP
• CSBP1
• CSBP2
• CSPB1
• MXI2
• SAPK2A
• RK
• p38
• CSBP
• EXIP
• Mxi2
• CSBP1
• CSBP2
• CSPB1
• PRKM14
• PRKM15
• SAPK2A
• p38ALPHA

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	1
biological term	1
chemical	1
drug	1
hub protein	1

Protein Classes

PANTHER Classes

Protein / Transferase / Kinase / Protein Kinase / Non-receptor Serine/threonine Protein Kinase / Mitogen-activated Protein Kinase 14

DTO Classes

Protein / Kinase / Protein Kinase / Cmgc Group / Mapk Family / P38 Subfamily / Mitogen-activated Protein Kinase 14

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 2473   (req: < 5)

Gene RIFs: 954   (req: <= 3)

Antibodies: 2029   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 2473   (req: >= 5)

Gene RIFs: 954   (req: > 3)

Antibodies: 2029   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 67

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 1552

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drugs: 2

Expression Data (0 Tissues)

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No expression data found

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Related Tools (5)

ProKinO

The ProKinO is a protein kinase-specific ontology, which provides a controlled vocabulary of terms, their hierarchy, and relationships unifying sequence, structure, function, mutation and pathway information on kinases.

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Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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Approved Drugs (2)

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1 – 2 of 2

dasatinib

MAPK14Tchem Kinase

INHIBITOR pKd : 7.89

sorafenib

MAPK14Tchem Kinase

INHIBITOR pKd : 7.8

Active Ligands (1552)

Explore Active Ligands

1 – 10 of 1552

staurosporine

MAPK14Tchem Kinase

pKd : 7.89

AST-487

MAPK14Tchem Kinase

pKd : 7.77

PD166285

MAPK14Tchem Kinase

pKi : 8.1

CHEMBL2347053

MAPK14Tchem Kinase

pIC50 : 9.4

SB203580

MAPK14Tchem Kinase

pKd : 7.6

doramapimod

MAPK14Tchem Kinase

pKd : 7.7

7-hydroxystaurosporine

MAPK14Tchem Kinase

pIC50 : 8.01

CHEMBL2151321

MAPK14Tchem Kinase

pIC50 : 8.92

pexmetinib

MAPK14Tchem Kinase

pKd : 6.17

PP1

MAPK14Tchem Kinase

pKi : 8

Protein-Protein Interactions (690)

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1 – 10 of 690

• See Interactions on String-DB

MAPKAPK3

Tchem

Family:  Kinase

Novelty:  0.02469147

p_int:  1

Score:  0.995

Data Source:  BioPlex,Reactome,STRINGDB

MKNK1

Tchem

Family:  Kinase

Novelty:  0.01445137

p_int:  1

Score:  0.981

Data Source:  BioPlex,STRINGDB

MAPKAPK2

Tchem

Family:  Kinase

Novelty:  0.00486452

p_int:  0.999999994

p_ni:  6e-9

Score:  0.997

Data Source:  BioPlex,Reactome,STRINGDB

DUSP9

Tbio

Family:  Enzyme

Novelty:  0.03849148

p_int:  0.999999985

p_ni:  4e-9

p_wrong:  1.1e-8

Score:  0.982

Data Source:  BioPlex,STRINGDB

RPS6KA4

Tchem

Family:  Kinase

Novelty:  0.05213255

p_int:  0.999999903

p_ni:  9.7e-8

Score:  0.965

Data Source:  BioPlex,STRINGDB

HOXC9

Tbio

Family:  TF

Novelty:  0.02524418

p_int:  0.999999741

p_ni:  2.58e-7

p_wrong:  1e-9

Data Source:  BioPlex

RPS6KA5

Tchem

Family:  Kinase

Novelty:  0.00811496

p_int:  0.99999934

p_ni:  6.6e-7

Score:  0.963

Data Source:  BioPlex,Reactome,STRINGDB

MAP2K3

Tchem

Family:  Kinase

Novelty:  0.00349605

p_int:  0.99999906

p_ni:  9.4e-7

Score:  0.989

Data Source:  BioPlex,Reactome,STRINGDB

DUSP7

Tbio

Family:  Enzyme

Novelty:  0.05499898

p_int:  0.999998932

p_ni:  2.59e-7

p_wrong:  8.09e-7

Score:  0.933

Data Source:  BioPlex,STRINGDB

CUL7

Tbio

Novelty:  0.02183958

p_int:  0.999998204

p_ni:  0.000001796

Score:  0.776

Data Source:  BioPlex,STRINGDB

Nearest Tclin Targets (10)

Explore Nearest Tclin Targets

Upstream (3)

Downstream (7)

1 – 3 of 3

BRAF

Tclin

Family:  Kinase

KEGG Distance:  1

Common Pathways:  8

1: Endocrine resistance

2: Neurotrophin signaling pathway

3: FoxO signaling pathway

4: Rap1 signaling pathway

more:  4 more common pathways

RAF1

Tclin

Family:  Kinase

KEGG Distance:  1

Common Pathways:  23

1: Endocrine resistance

2: Relaxin signaling pathway

3: T cell receptor signaling pathway

4: Fc epsilon RI signaling pathway

more:  19 more common pathways

PGR

Tclin

Family:  Nuclear Receptor

KEGG Distance:  1

Common Pathways:  2

1: Oocyte meiosis

2: Progesterone-mediated oocyte maturation

Pathways (265)

Reactome (69)

KEGG (51)

PathwayCommons (84)

WikiPathways (61)

ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	ADP signalling through P2Y purinoceptor 1	25 targets	R-HSA-418592
Reactome	Activation of PPARGC1A (PGC-1alpha) by phosphorylation	10 targets	R-HSA-2151209
Reactome	Activation of the AP-1 family of transcription factors	10 targets	R-HSA-450341
Reactome	Axon guidance	533 targets	R-HSA-422475
Reactome	Cellular Senescence	164 targets	R-HSA-2559583

Name	Explore in Pharos	Explore in Source
ADP signalling through P2Y purinoceptor 1	25 targets	R-HSA-418592
Activation of PPARGC1A (PGC-1alpha) by phosphorylation	10 targets	R-HSA-2151209
Activation of the AP-1 family of transcription factors	10 targets	R-HSA-450341
Axon guidance	533 targets	R-HSA-422475
Cellular Senescence	164 targets	R-HSA-2559583

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (78)

Functions (8)

Components (11)

Processes (59)

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1 – 8 of 8

GO Term	Evidence	Assigned by
MAP kinase activity	Inferred from Direct Assay (IDA)	UniProtKB
enzyme binding	Inferred from Physical Interaction (IPI)	BHF-UCL
mitogen-activated protein kinase p38 binding	Inferred from Physical Interaction (IPI)	UniProtKB
protein phosphatase binding	Inferred from Physical Interaction (IPI)	UniProtKB
NFAT protein binding	Inferred from Sequence or structural Similarity (ISS)	BHF-UCL
MAP kinase kinase activity	Traceable Author Statement (TAS)	ProtInc
protein serine/threonine kinase activity	Traceable Author Statement (TAS)	Reactome
ATP binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW

Disease Associations (null)

No disease associations found

GWAS Traits (10)

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5

1 – 5 of 10

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
appendicular lean mass	EFO_0004980	1	1	1		60.5
diabetic foot	EFO_1001459	1	1	0	1.7	47.5
body height	EFO_0004339	1	1	1		39.5
age at menopause	EFO_0004704	2	1	2		30.6
BMI-adjusted waist circumference	EFO_0007789	1	2	2		22.5

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 10

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
appendicular lean mass	EFO_0004980	1		60.5
diabetic foot	EFO_1001459	0	1.7	47.5
body height	EFO_0004339	1		39.5
age at menopause	EFO_0004704	2		30.6
BMI-adjusted waist circumference	EFO_0007789	2		22.5

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UniProt Keyword Find Similar Targets

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3D-structure
Acetylation
Alternative splicing
Apoptosis
ATP-binding
Complete proteome
Cytoplasm
Direct protein sequencing
Kinase
Nucleotide-binding

GWAS Trait Find Similar Targets

No Header	No Header
age at menopause
antisocial behaviour measurement
appendicular lean mass
attention deficit hyperactivity disorder
BMI-adjusted waist circumference
body height
diabetic foot
mean corpuscular volume
rheumatoid arthritis
substance abuse

MGI Phenotype Find Similar Targets

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behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
embryo phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
integument phenotype

IDG Resources

No IDG generated resources found

Orthologs (11)

1 – 5 of 11

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	mitogen-activated protein kinase 14	VGNC:7197	450161
Macaque	mitogen-activated protein kinase 14		718976
Mouse	mitogen-activated protein kinase 14	MGI:1346865	26416
Rat	mitogen activated protein kinase 14	RGD:70496	81649
Dog	mitogen-activated protein kinase 14	VGNC:42995	403856

Species	Name	OMA	EggNOG	Inparanoid
Chimp	mitogen-activated protein kinase 14
Macaque	mitogen-activated protein kinase 14
Mouse	mitogen-activated protein kinase 14
Rat	mitogen activated protein kinase 14
Dog	mitogen-activated protein kinase 14

Publication Statistics

PubMed Score 2473.00

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PubTator Score 5625.92

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Text Mined References (1128)

GeneRif Annotations (954)

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PMID	Year	Title