Q9WUI1 (MK11_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 121. History...
Names and origin
|Protein names||Recommended name:|
Mitogen-activated protein kinase 11
Short name=MAP kinase 11
Short name=MAPK 11
Mitogen-activated protein kinase p38 beta
Short name=MAP kinase p38 beta
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||364 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. Ref.4
ATP + a protein = ADP + a phosphoprotein.
Magnesium By similarity.
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. Ref.5
Interacts with HDAC3 and DUSP16 By similarity.
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme. Ref.5
Contains 1 protein kinase domain.
|Biological process||Stress response|
|Technical term||Complete proteome|
|Gene Ontology (GO)|
|Biological_process||intracellular signal transductionregulation of transcription, DNA-templated|
Inferred from electronic annotation. Source: UniProtKB-KWresponse to stress
Inferred from electronic annotation. Source: UniProtKB-KWtranscription, DNA-templated
Inferred from electronic annotation. Source: UniProtKB-KW
Traceable author statement. Source: Reactomenucleus
Inferred from electronic annotation. Source: UniProtKB-SubCell
Inferred from electronic annotation. Source: UniProtKB-KWMAP kinase activityprotein binding
|Complete GO annotation...|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 364||364||Mitogen-activated protein kinase 11||PRO_0000186281|
|Domain||24 – 308||285||Protein kinase|
|Nucleotide binding||30 – 38||9||ATP By similarity|
|Region||106 – 110||5||Inhibitor-binding By similarity|
|Region||168 – 169||2||Inhibitor-binding By similarity|
|Motif||180 – 182||3||TXY|
|Active site||168||1||Proton acceptor By similarity|
|Binding site||53||1||ATP By similarity|
|Binding site||71||1||Nilotinib By similarity|
Amino acid modifications
|Modified residue||180||1||Phosphothreonine; by MAP2K3, MAP2K4 and MAP2K6 Probable|
|Modified residue||182||1||Phosphotyrosine; by MAP2K3, MAP2K4 and MAP2K6 Probable|
|Modified residue||323||1||Phosphotyrosine; by ZAP70 By similarity|
|Sequence conflict||173||1||R → P in AAD30116. Ref.1|
|Sequence conflict||312||1||H → R in AAD30116. Ref.1|
|||"The primary structure of murine p38beta."|
Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.|
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
|||"MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts."|
Wiggin G.R., Soloaga A., Foster J.M., Murray-Tait V., Cohen P., Arthur J.S.
Mol. Cell. Biol. 22:2871-2881(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF RPS6KA5/MSK1 AND RPS6KA4/MSK2.
|||"Differential activation of p38MAPK isoforms by MKK6 and MKK3."|
Remy G., Risco A.M., Inesta-Vaquera F.A., Gonzalez-Teran B., Sabio G., Davis R.J., Cuenda A.
Cell. Signal. 22:660-667(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, ENZYME REGULATION.
|||"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.
|||"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.|
|AF135185 mRNA. Translation: AAD30116.1.|
CH466550 Genomic DNA. Translation: EDL04368.1.
BC092526 mRNA. Translation: AAH92526.1.
|RefSeq||NP_035291.4. NM_011161.5. |
3D structure databases
|SMR||Q9WUI1. Positions 3-349. |
Protein-protein interaction databases
|IntAct||Q9WUI1. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000088823; ENSMUSP00000086204; ENSMUSG00000053137. |
|UCSC||uc007xfp.2. mouse. |
|MGI||MGI:1338024. Mapk11. |
Enzyme and pathway databases
|Reactome||REACT_188576. Developmental Biology. |
REACT_217867. Metabolism of RNA.
REACT_224594. Organelle biogenesis and maintenance.
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|PRINTS||PR01773. P38MAPKINASE. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS01351. MAPK. 1 hit. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
|Accession||Primary (citable) accession number: Q9WUI1|
Secondary accession number(s): Q569F1
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|