MAPKAPK2 (mitogen-activated protein kinase-activated protein kinase 2)

2010-04-01   Roberta Felix , Veruska Alves , Andre Vettore , Gisele Colleoni 

Laboratory of Cancer Molecular Biology, Federal University of Sao Paulo UNIFESP\\\/EPM, Sao Paulo, Brazil





MAPKAPK2 encodes a member of the Ser/Thr protein kinase regulated through direct phosphorylation by p38 MAP kinase. Inhibition of the p38 MAPK pathway could be a possible target to inflammatory diseases therapy. Unfortunately, blocking p38 MAPK activation "in vivo" implies in high toxicity and it does not have oral bioavailability. MAPKAPK2/MK2 inhibitors acting downstream of p38 could be reasonable solutions to overcome this problem (Duraisamy et al., 2008).


Size 49,338 bases, starts at 204924912 and ends at 204974256 bp from pter with plus strand orientation.


We found some discordant information regarding MAPKAPK2 splice variants. Kervinen et al. 2006, described that the human MAPKAPK2 gene encodes two alternatively spliced transcripts and also that this gene contains 14 different introns (13 gt-ag, 1 gc-ag). Transcription produces 9 different mRNAs, 8 alternatively spliced variants and 1 unspliced form. There are 5 probable alternative promoters and 3 validated alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 5 end, presence or absence of 7 cassette exons, overlapping exons with different boundaries, alternative splicing or retention of 3 introns.


ATF4C - Cyclic AMP-dependent transcription factor ATF-4, localized at chromosome 17, location: 17q25.1.



MAPKAPK2 has two alternatively spliced transcripts, encoding 400 and 370 amino acids, with sequence heterogeneity from Lys-353 to the C-terminus. Crystal structure shows: 1) an autoinhibitory domain, consisting of 328-370 residues; 2) a helix-turn-helix structure that occupies the substrate-binding cleft of the kinase domain and inhibits kinase function (ter Haar et al., 2007).


The 400-residue MAPKAPK2 (isoform 1) consists of an N-terminal Pro-rich region, a kinase domain, an autoinhibitory domains, and C-terminal nuclear export (NES) and nuclear localization (NLS) signals. The 1-370 isoform (isoform 2) lacks NES and NLS, consistent with its presence only in the cytoplasm. MAPKAPK2 also phosphorylates proteins found in both the nucleus (cAMP-response element-binding protein, or CREB) and cytoplasm (HSP25/27 and LSP-1) (Kervinen et al., 2006).


MAPKAPK2 is required for both cytokines production and cell migration (Kotlyarov et al., 2002).
MAPKAPK2 is activated upon stress by p38 MAPK, which binds C terminus of MAPKAPK2, leading to subsequently phosphorylation of its regulatory sites. After activation, MAPKAPK2 is transferred from nucleus to cytoplasm, and cotransport p38 to the new localization. In murine knockout model, MAPKAPK2 blockage leads to a dramatic reduction of tumor necrosis factor (TNF) production in response to lipopolysaccharide (Kotlyarov et al., 2002). One of the major substrates of MAPKAPK2 is the heat shock protein HSP27, which stimulates actin polymerization in order to facilitate recovery from destruction of cytoskeleton during cellular stresses.


Isoform 1 and 2 see figure below.
Atlas Image



There is one described mutation: position 804 of mRNA, allele change GCC to GGC. At protein level, residue change A [Ala] to G [Gly].

Implicated in

Entity name
Hideshima et al. 2004 have shown that overexpression of HSP27 confers resistance to bortezomib, a proteasome inhibitor currently used as front line MM therapy, combined with corticosteroids and immunomodulatory drugs, such as thalidomide and lenalidomide. Therefore, overexpression of MAPKAPK2 could be related to MM resistance to chemotherapy. They hypothesized that inhibition of MAPKAPK2 activity could augment bortezomib cytotoxicity by down regulating HSP27. Felix et al. 2009, at their gene expression studies, supported further exploitation of this pathway as therapeutic target in MM, although immunohistochemistry did not show high frequency of protein expression in MM (21%) (Felix et al., 2009).
Atlas Image
Panel showing bone marrow samples of MM cases: A - plasma cells nuclear and cytoplasmatic positivity for MAPKAPK2; B - sample negative for MAPKAPK2 (400X).
Entity name
Bladder cancer
Kumar et al. 2010, showed that overexpression of the matrix metalloproteinases MMP-2 and MMP-9 have prognostic value in transitional cell carcinoma of bladder. p38 MAPK modulated MMP-2/9 mRNA expression and MMP-2/9 activity as mediators of tumor cells invasive capacity. Therefore, p38 MAPK inhibition blocks MMP-2/9 activities mediated by MAPKAPK2 (Kumar et al., 2010).
Entity name
Skin tumor
Using the two-stage chemical carcinogenesis model, Johansen et al. 2009 studied the effect of MAPKAPK2-deficiency and TNF-alpha-deficiency on skin tumor development in mice. Their findings demonstrate a dual role of MAPKAPK2 in the early stages of tumor promotion through regulation of both the inflammatory response and apoptosis of DNA-damaged cells. These results also identify MAPKAPK2 as a possible target for skin carcinoma therapy (Johansen et al., 2009).
Entity name
Prostate cancer
TGFbeta is an important regulator of cell adhesion and motility in a variety of cell types. p38 MAP kinase is necessary for TGFbeta -mediated up-regulation of matrix metalloproteinase type 2 (MMP-2), as well as TGFbeta -dependent increases in prostate cell invasion. Xu et al. 2006 demonstrated, after transient transfection, that both MAPKAPK2 and HSP27 are necessary for TGFbeta -mediated increases in MMP-2 activity in any cell type, as well as prostate cancer cells (Xu et al., 2006).
Entity name
Alzheimers disease (AD)
Culbert et al. 2006 suggested that MAPKAPK2 plays a role in neuroinflammatory and neurodegenerative diseases, such as AD. The MAPKAPK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon gamma-stimulated microglial cells, demonstrating MAPKAPK2 ability in eliciting a pro-inflammatory response. Again, MAPKAPK2 pathway can be considered a target for control of this degenerative brain disease.
Entity name
Psoriatic skin
Alterations in this specific signal transduction pathway may be involved in increased expression of proinflammatory cytokines in inflammatory diseases (Johansen et al., 2006). The increased activation of MAPKAPK2 is responsible for the elevated TNFalpha protein expression in psoriatic skin, making this pathway a potential target in the treatment of psoriasis (Johansen et al., 2006).


Pubmed IDLast YearTitleAuthors
167749242006MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease.Culbert AA et al
186205162008MK2: a novel molecular target for anti-inflammatory therapy.Duraisamy S et al
191714222009SAGE analysis highlights the importance of p53csv, ddx5, mapkapk2 and ranbp2 to multiple myeloma tumorigenesis.Felix RS et al
154804252004p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells.Hideshima T et al
198088572009MK2 regulates the early stages of skin tumor promotion.Johansen C et al
166207702006Effect of construct design on MAPKAP kinase-2 activity, thermodynamic stability and ligand-binding affinity.Kervinen J et al
120528892002Distinct cellular functions of MK2.Kotlyarov A et al
200681722010p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity.Kumar B et al
164078302006MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer.Xu L et al
172550972007Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer.Haar ET et al

Other Information

Locus ID:

NCBI: 9261
MIM: 602006
HGNC: 6887
Ensembl: ENSG00000162889


dbSNP: 9261
ClinVar: 9261
TCGA: ENSG00000162889


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
VEGF signaling pathwayKEGGko04370
MAPK signaling pathwayKEGGhsa04010
VEGF signaling pathwayKEGGhsa04370
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
activated TAK1 mediates p38 MAPK activationREACTOMER-HSA-450302
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
CREB phosphorylationREACTOMER-HSA-199920
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
p38MAPK eventsREACTOMER-HSA-171007
Nuclear Events (kinase and transcription factor activation)REACTOMER-HSA-198725
Signaling by VEGFREACTOMER-HSA-194138
Gene ExpressionREACTOMER-HSA-74160
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNAREACTOMER-HSA-450385
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNAREACTOMER-HSA-450513
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Arachidonic acid metabolismREACTOMER-HSA-2142753
Synthesis of Leukotrienes (LT) and Eoxins (EX)REACTOMER-HSA-2142691
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
Regulation of HSF1-mediated heat shock responseREACTOMER-HSA-3371453
Cellular SenescenceREACTOMER-HSA-2559583
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
156297152005MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.144
262805352015mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.123
156920532005The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs.98
202121542010p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication.86
209324732010DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization.86
210788772011Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment.80
164078302006MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer.71
200681722010p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity.66
205953892010MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment.63
216061982011A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage.63


Roberta Felix ; Veruska Alves ; Andre Vettore ; Gisele Colleoni

MAPKAPK2 (mitogen-activated protein kinase-activated protein kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

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