Target Information
Target General Infomation | |||||
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Target ID |
T21307
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Former ID |
TTDI02119
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Target Name |
MAPKAP kinase 2
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Gene Name |
MAPKAPK2
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Synonyms |
MAP kinaseactivated protein kinase 2; MAPKactivated protein kinase 2; MK2; MAPKAPK2
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Target Type |
Clinical Trial
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Disease | Autoimmune diabetes [ICD10: E08-E13] | ||||
Fibrosis [ICD9: 709.2; ICD10: L90.5] | |||||
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25] | |||||
Mesothelioma [ICD9: 163; ICD10: C45] | |||||
Function |
Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat- shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.
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BioChemical Class |
Kinase
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAII
DDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRI VDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQYLHSI NIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKY DKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKM LIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKEEMTSAL ATMRVDYEQIKIKKIEDASNPLLLKRRKKARALEAAALAH |
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Drugs and Mode of Action | |||||
Inhibitor | CBP-501 | Drug Info | [550418] | ||
CMPD1 | Drug Info | [529123] | |||
compound 16 | Drug Info | [528819] | |||
compound 16 | Drug Info | [529760] | |||
compound 33 | Drug Info | [530078] | |||
MAPKAP kinase 2 inhibitors | Drug Info | [543553] | |||
MK2 inhibitors | Drug Info | [543553] | |||
MMI-0100 | Drug Info | [543553] | |||
PF-3644022 | Drug Info | [530792] | |||
Research programme: MAP kinase kinase 2 inhibitors, Pfizer | Drug Info | [543553] | |||
Pathways | |||||
KEGG Pathway | MAPK signaling pathway | ||||
VEGF signaling pathway | |||||
Neurotrophin signaling pathway | |||||
Viral carcinogenesis | |||||
NetPath Pathway | IL2 Signaling Pathway | ||||
PANTHER Pathway | Angiogenesis | ||||
Interleukin signaling pathway | |||||
PDGF signaling pathway | |||||
VEGF signaling pathway | |||||
Ras Pathway | |||||
p38 MAPK pathway | |||||
Pathway Interaction Database | IL2-mediated signaling events | ||||
p38 signaling mediated by MAPKAP kinases | |||||
Signaling mediated by p38-alpha and p38-beta | |||||
Signaling events mediated by VEGFR1 and VEGFR2 | |||||
Trk receptor signaling mediated by the MAPK pathway | |||||
Reactome | p38MAPK events | ||||
Oxidative Stress Induced Senescence | |||||
Regulation of HSF1-mediated heat shock response | |||||
VEGFA-VEGFR2 Pathway | |||||
activated TAK1 mediates p38 MAPK activation | |||||
WikiPathways | Serotonin Receptor 4/6/7 and NR3C Signaling | ||||
Serotonin Receptor 2 and ELK-SRF/GATA4 signaling | |||||
Serotonin HTR1 Group and FOS Pathway | |||||
p38 MAPK Signaling Pathway | |||||
MAPK Signaling Pathway | |||||
FAS pathway and Stress induction of HSP regulation | |||||
MAP kinase activation in TLR cascade | |||||
Regulation of mRNA Stability by Proteins that Bind AU-rich Elements | |||||
Arachidonic acid metabolism | |||||
Structural Pathway of Interleukin 1 (IL-1) | |||||
Regulation of Microtubule Cytoskeleton | |||||
IL-1 signaling pathway | |||||
NGF signalling via TRKA from the plasma membrane | |||||
MAPK targets/ Nuclear events mediated by MAP kinases | |||||
References | |||||
Ref 528819 | J Med Chem. 2007 May 31;50(11):2647-54. Epub 2007 May 5.Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). | ||||
Ref 529123 | Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38alpha(MAPK) inhibitors in Werner syndrome cells. Bioorg Med Chem Lett. 2007 Dec 15;17(24):6832-5. Epub 2007 Oct 17. | ||||
Ref 529760 | Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity. Bioorg Med Chem Lett. 2008 Dec 1;18(23):6142-6. | ||||
Ref 530078 | Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem. 2009 May 1;17(9):3342-51. | ||||
Ref 530792 | A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J Pharmacol Exp Ther. 2010 Jun;333(3):797-807. |
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