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Protein

Mitogen-activated protein kinase 11

Gene

MAPK11

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK11 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. MAPK11 functions are mostly redundant with those of MAPK14. 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. 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. 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. Additional examples of p38 MAPK substrates are the 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.5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Enzyme regulationi

Activated by phosphorylation on threonine and tyrosine by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 induced by environmental stress. HDAC3 interacts directly and selectively with MAPK11 to repress ATF2 transcriptional activity, and regulate TNF gene expression in LPS-stimulated cells. Inhibited by SB203580 and pyridinyl-imidazole related compounds.4 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei53ATPPROSITE-ProRule annotation1
Binding sitei71Nilotinib1
Active sitei150Proton acceptorPROSITE-ProRule annotation1

Regions

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

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • MAP kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: Reactome

GO - Biological processi

  • activation of MAPK activity Source: Reactome
  • cellular response to interleukin-1 Source: UniProtKB
  • cellular response to virus Source: UniProtKB
  • negative regulation of cardiac muscle cell proliferation Source: Ensembl
  • positive regulation of gene expression Source: UniProtKB
  • positive regulation of interleukin-12 secretion Source: UniProtKB
  • positive regulation of muscle cell differentiation Source: Reactome
  • regulation of signal transduction by p53 class mediator Source: Reactome
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • stress-activated MAPK cascade Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.11.24 2681
ReactomeiR-HSA-168638 NOD1/2 Signaling Pathway
R-HSA-171007 p38MAPK events
R-HSA-198753 ERK/MAPK targets
R-HSA-2151209 Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-2559580 Oxidative Stress Induced Senescence
R-HSA-375170 CDO in myogenesis
R-HSA-376172 DSCAM interactions
R-HSA-4420097 VEGFA-VEGFR2 Pathway
R-HSA-450302 activated TAK1 mediates p38 MAPK activation
R-HSA-450341 Activation of the AP-1 family of transcription factors
R-HSA-450604 KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation
SignaLinkiQ15759
SIGNORiQ15759

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 11 (EC:2.7.11.24)
Short name:
MAP kinase 11
Short name:
MAPK 11
Alternative name(s):
Mitogen-activated protein kinase p38 beta
Short name:
MAP kinase p38 beta
Short name:
p38b
Stress-activated protein kinase 2b
Short name:
SAPK2b
p38-2
Gene namesi
Name:MAPK11
Synonyms:PRKM11, SAPK2, SAPK2B
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 22

Organism-specific databases

EuPathDBiHostDB:ENSG00000185386.14
HGNCiHGNC:6873 MAPK11
MIMi602898 gene
neXtProtiNX_Q15759

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi180T → A: Inactivation. 1
Mutagenesisi182Y → F: Inactivation. 1

Organism-specific databases

DisGeNETi5600
OpenTargetsiENSG00000185386
PharmGKBiPA30618

Chemistry databases

ChEMBLiCHEMBL3961
DrugBankiDB05157 KC706
DB08896 Regorafenib
GuidetoPHARMACOLOGYi1500

Polymorphism and mutation databases

BioMutaiMAPK11
DMDMi134047835

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001862801 – 364Mitogen-activated protein kinase 11Add BLAST364

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei180Phosphothreonine; by MAP2K3, MAP2K4 and MAP2K61 Publication1
Modified residuei182Phosphotyrosine; by MAP2K3, MAP2K4 and MAP2K61 Publication1
Modified residuei323Phosphotyrosine; by ZAP70By similarity1

Post-translational modificationi

Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ15759
PaxDbiQ15759
PeptideAtlasiQ15759
PRIDEiQ15759

PTM databases

iPTMnetiQ15759
PhosphoSitePlusiQ15759

Expressioni

Tissue specificityi

Highest levels in the brain and heart. Also expressed in the placenta, lung, liver, skeletal muscle, kidney and pancreas.

Gene expression databases

BgeeiENSG00000185386
CleanExiHS_MAPK11
ExpressionAtlasiQ15759 baseline and differential
GenevisibleiQ15759 HS

Organism-specific databases

HPAiCAB012961
HPA045069

Interactioni

Subunit structurei

Interacts with HDAC3 and DUSP16.3 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi111586, 34 interactors
IntActiQ15759, 21 interactors
MINTiQ15759
STRINGi9606.ENSP00000333685

Chemistry databases

BindingDBiQ15759

Structurei

Secondary structure

1364
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi8 – 15Combined sources8
Beta strandi17 – 21Combined sources5
Beta strandi24 – 29Combined sources6
Beta strandi31 – 33Combined sources3
Turni34 – 37Combined sources4
Beta strandi38 – 43Combined sources6
Turni44 – 47Combined sources4
Beta strandi48 – 54Combined sources7
Helixi62 – 77Combined sources16
Beta strandi86 – 90Combined sources5
Helixi96 – 98Combined sources3
Beta strandi103 – 107Combined sources5
Beta strandi110 – 112Combined sources3
Helixi113 – 119Combined sources7
Helixi124 – 143Combined sources20
Helixi153 – 155Combined sources3
Beta strandi156 – 158Combined sources3
Beta strandi164 – 166Combined sources3
Helixi179 – 182Combined sources4
Helixi185 – 188Combined sources4
Helixi191 – 194Combined sources4
Helixi203 – 218Combined sources16
Helixi228 – 239Combined sources12
Helixi244 – 249Combined sources6
Turni253 – 255Combined sources3
Helixi256 – 260Combined sources5
Helixi270 – 273Combined sources4
Turni274 – 276Combined sources3
Helixi279 – 285Combined sources7
Turni286 – 288Combined sources3
Helixi293 – 295Combined sources3
Helixi299 – 302Combined sources4
Helixi306 – 308Combined sources3
Turni309 – 311Combined sources3
Helixi314 – 316Combined sources3
Helixi326 – 329Combined sources4
Helixi334 – 347Combined sources14

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3GC8X-ray2.40A/B1-364[»]
3GC9X-ray2.05A/B1-364[»]
3GP0X-ray1.90A5-350[»]
ProteinModelPortaliQ15759
SMRiQ15759
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15759

Family & Domainsi

Domains and Repeats

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

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni106 – 110Inhibitor-binding5
Regioni168 – 169Inhibitor-binding2

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi180 – 182TXY3

Domaini

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

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0660 Eukaryota
ENOG410XNY0 LUCA
GeneTreeiENSGT00550000074271
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiQ15759
KOiK04441
OMAiASDEPDC
OrthoDBiEOG091G08QL
PhylomeDBiQ15759
TreeFamiTF105100

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR003527 MAP_kinase_CS
IPR008352 MAPK_p38-like
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
PRINTSiPR01773 P38MAPKINASE
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS01351 MAPK, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit

Sequences (2)i

Sequence statusi: Complete.

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

Isoform 1 (identifier: Q15759-1) [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

        10         20         30         40         50
MSGPRAGFYR QELNKTVWEV PQRLQGLRPV GSGAYGSVCS AYDARLRQKV
60 70 80 90 100
AVKKLSRPFQ SLIHARRTYR ELRLLKHLKH ENVIGLLDVF TPATSIEDFS
110 120 130 140 150
EVYLVTTLMG ADLNNIVKCQ ALSDEHVQFL VYQLLRGLKY IHSAGIIHRD
160 170 180 190 200
LKPSNVAVNE DCELRILDFG LARQADEEMT GYVATRWYRA PEIMLNWMHY
210 220 230 240 250
NQTVDIWSVG CIMAELLQGK ALFPGSDYID QLKRIMEVVG TPSPEVLAKI
260 270 280 290 300
SSEHARTYIQ SLPPMPQKDL SSIFRGANPL AIDLLGRMLV LDSDQRVSAA
310 320 330 340 350
EALAHAYFSQ YHDPEDEPEA EPYDESVEAK ERTLEEWKEL TYQEVLSFKP
360
PEPPKPPGSL EIEQ
Length:364
Mass (Da):41,357
Last modified:March 20, 2007 - v2
Checksum:i68DA4C7B7C721475
GO
Isoform 2 (identifier: Q15759-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-108: Missing.
     204-321: VDIWSVGCIM...HDPEDEPEAE → GAGGRPWGDE...GYLVRGLHHG
     322-364: Missing.

Note: No experimental confirmation available.
Show »
Length:213
Mass (Da):23,603
Checksum:iE3466E25BE1D27A3
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti98D → V in BAF84534 (PubMed:14702039).Curated1
Sequence conflicti122 – 123LS → GAHQGARLAL in AAB05036 (PubMed:8663524).Curated2
Sequence conflicti326S → G in AAB66313 (PubMed:9235954).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_042264221A → V in a lung neuroendocrine carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_025176275R → H2 PublicationsCorresponds to variant dbSNP:rs33932986Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0552211 – 108Missing in isoform 2. 1 PublicationAdd BLAST108
Alternative sequenceiVSP_055222204 – 321VDIWS…EPEAE → GAGGRPWGDEGQGPRLALDW LCMPGLRGQARSPRMWDPHS KVALQRPLEHDGCWPPLAVQ LWTSPCLGGLGMAEEGVCPS WGLDVTVGLLEEGRGVGTLM EVPSPSHSGYLVRGLHHG in isoform 2. 1 PublicationAdd BLAST118
Alternative sequenceiVSP_055223322 – 364Missing in isoform 2. 1 PublicationAdd BLAST43

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U53442 mRNA Translation: AAB05036.1
AF001008 mRNA Translation: AAC51250.1
AF001174 mRNA Translation: AAC51373.1
AF031135 mRNA Translation: AAC12714.1
Y14440 mRNA Translation: CAA74792.1
U92268 mRNA Translation: AAB66313.1
CR456514 mRNA Translation: CAG30400.1
DQ279722 Genomic DNA Translation: ABB72677.1
AK291845 mRNA Translation: BAF84534.1
AK299745 mRNA Translation: BAH13116.1
EU332851 Genomic DNA Translation: ABY87540.1
JX512451 Genomic DNA Translation: AGC09598.1
AL022328 Genomic DNA No translation available.
CH471138 Genomic DNA Translation: EAW73524.1
CH471138 Genomic DNA Translation: EAW73525.1
CH471138 Genomic DNA Translation: EAW73526.1
BC027933 mRNA Translation: AAH27933.1
CCDSiCCDS14090.1 [Q15759-1]
PIRiG02524
JC5529
RefSeqiNP_002742.3, NM_002751.6 [Q15759-1]
UniGeneiHs.57732

Genome annotation databases

EnsembliENST00000330651; ENSP00000333685; ENSG00000185386 [Q15759-1]
ENST00000395764; ENSP00000379113; ENSG00000185386 [Q15759-1]
GeneIDi5600
KEGGihsa:5600
UCSCiuc003bkr.4 human [Q15759-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiMK11_HUMAN
AccessioniPrimary (citable) accession number: Q15759
Secondary accession number(s): A8K730
, B0LPG1, B7Z630, E7ETQ1, L7RT27, O00284, O15472, Q2XNF2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: March 20, 2007
Last modified: May 23, 2018
This is version 189 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 22
    Human chromosome 22: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

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