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mitogen-activated protein kinase 13

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1502

Nomenclature: mitogen-activated protein kinase 13

Abbreviated Name: p38δ

Family: p38 subfamily

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 365 6p21.31 MAPK13 mitogen-activated protein kinase 13
Mouse - 366 17 A3.3 Mapk13 mitogen-activated protein kinase 13
Rat - 366 20p12 Mapk13 mitogen activated protein kinase 13
Previous and Unofficial Names Click here for help
SAPK4 | MAP kinase 13 | MAP kinase p38 delta | MAPK 13 | mitogen-activated protein kinase p38 delta | stress-activated protein kinase 4 | Serk4 | p38 delta MAP kinase | p38delta | PRKM13
Database Links Click here for help
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of p38delta kinase
PDB Id:  3COI
Resolution:  2.09Å
Species:  Human
References: 
Image of receptor 3D structure from RCSB PDB
Description:  MAPK13 Complex with inhibitor
PDB Id:  4EYJ
Resolution:  2.1Å
Species:  Human
References:  1
Enzyme Reaction Click here for help
EC Number: 2.7.11.24

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PF-03715455 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.6 pIC50 12
pIC50 7.6 (IC50 2.3x10-8 M) [12]
MAPK13-IN-1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.2 – 7.1 pIC50 1,9
pIC50 7.1 (IC50 8.272x10-8 M) [9]
Description: Determined using an IMAP-based biochemical assay.
pIC50 6.2 (IC50 6.2x10-7 M) [1]
doramapimod Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.5 pIC50 13
pIC50 6.5 (IC50 3x10-7 M) [13]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,19

Key to terms and symbols Click column headers to sort
Target used in screen: p38-delta
Ligand Sp. Type Action Value Parameter
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.9 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.2 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
masitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 2,6

Key to terms and symbols Click column headers to sort
Target used in screen: SAPK4/P38d(MAPK13)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 77.1 43.0 46.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 86.6 21.5 3.5
GSK-3 inhibitor IX Small molecule or natural product Hs Inhibitor Inhibition 87.5 89.0 92.0
vatalanib Small molecule or natural product Hs Inhibitor Inhibition 88.9
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 89.5
AG 1296 Small molecule or natural product Hs Inhibitor Inhibition 89.6 116.0 105.0
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 90.4
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 90.4 62.0 24.0
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 90.7
GSK-3beta inhibitor VIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 91.1 96.0 89.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
p38 MAP kinases are ubiquitous, highly conserved enzymes which regulate the production of proinflammatory mediators (such as TNFα and IL-1) in response to inflammatory cytokines or environmental stress [7-8,11,15-16,18]. They are essential for normal immune and inflammatory responses, but are also involved in many other cellular processes such as regulating the cell cycle and cytoskeletal remodelling.

Pharmacological inhibition of p38 MAP kinases reduces inflammatory cytokine synthesis, making these enzymes validated and extensively pursued drug targets for autoimmune and inflammatory diseases, including arthritis and other joint diseases, septic shock, myocardial injury and neuroinflammation. A number of pan-p38 MAP kinase inhibitors and isoform selective inhibitors have been evaluated in clinical trials, although none have yet reached the clinic.

MAPK13 displays a more tissue-specific expression pattern than MAPK14, and was therefore considered to offer a more defined drug target for specific biological pathways [14]. MAPK13 plays a role in diabetes [17], neutrophil chemotaxis pathways associated with acute respiratory distress syndrome (ARDS) [10], carcinogenesis [5,20] and IL-13-dependent airway mucous overproduction in chronic inflammatory lung disease [1].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0050729 positive regulation of inflammatory response IC
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0050729 positive regulation of inflammatory response IC
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0032755 positive regulation of interleukin-6 production IMP
GO:0071347 cellular response to interleukin-1 IDA
General Comments
SARS-CoV-2: p38 MAP kinase activity is reported to be upregulated by SARS-CoV-2 infection in vitro [3]. siRNA-mediated knockdown of MAPK13 (p38δ) in A549-ACE2 cells significantly reduces SARS-CoV-2 replication, without reducing cell viability. Pharmacological inhibition of p38δ also reduces SARS-CoV-2 replication.

References

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1. Alevy YG, Patel AC, Romero AG, Patel DA, Tucker J, Roswit WT, Miller CA, Heier RF, Byers DE, Brett TJ et al.. (2012) IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J. Clin. Invest., 122 (12): 4555-68. [PMID:23187130]

2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

3. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Marrero MC, Polacco BJ, Melnyk JE, Ulferts S, Kaake RM. (2020) The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell, Article Online Now. DOI: 10.1016/j.cell.2020.06.034

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

5. Del Reino P, Alsina-Beauchamp D, Escós A, Cerezo-Guisado MI, Risco A, Aparicio N, Zur R, Fernandez-Estévez M, Collantes E, Montans J et al.. (2014) Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer. Cancer Res., 74 (21): 6150-60. [PMID:25217523]

6. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

7. Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ. (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature, 386 (6622): 296-9. [PMID:9069290]

8. Han J, Lee JD, Bibbs L, Ulevitch RJ. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 265 (5173): 808-11. [PMID:7914033]

9. Holtzman MJ, Romero AD, Alevy YG, Patel AC, Brett TJ, Patel D. (2014) Anti-mucus drugs and uses therefor. Patent number: WO2014015056A2. Assignee: Washington University. Priority date: 17/07/2012. Publication date: 23/01/2014.

10. Ittner A, Block H, Reichel CA, Varjosalo M, Gehart H, Sumara G, Gstaiger M, Krombach F, Zarbock A, Ricci R. (2012) Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung. J. Exp. Med., 209 (12): 2229-46. [PMID:23129748]

11. Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. (2000) Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology, 47 (2-3): 185-201. [PMID:10878289]

12. Millan DS, Bunnage ME, Burrows JL, Butcher KJ, Dodd PG, Evans TJ, Fairman DA, Hughes SJ, Kilty IC, Lemaitre A et al.. (2011) Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease. J. Med. Chem., 54 (22): 7797-814. [PMID:21888439]

13. Moffett K, Konteatis Z, Nguyen D, Shetty R, Ludington J, Fujimoto T, Lee KJ, Chai X, Namboodiri H, Karpusas M et al.. (2011) Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD). Bioorg. Med. Chem. Lett., 21 (23): 7155-65. [PMID:22014550]

14. O'Callaghan C, Fanning LJ, Barry OP. (2014) p38δ MAPK: Emerging Roles of a Neglected Isoform. Int J Cell Biol, 2014: 272689. [PMID:25313309]

15. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev., 22 (2): 153-83. [PMID:11294822]

16. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem., 270 (13): 7420-6. [PMID:7535770]

17. Sumara G, Formentini I, Collins S, Sumara I, Windak R, Bodenmiller B, Ramracheya R, Caille D, Jiang H, Platt KA et al.. (2009) Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell, 136 (2): 235-48. [PMID:19135240]

18. Wang XZ, Ron D. (1996) Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science, 272 (5266): 1347-9. [PMID:8650547]

19. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

20. Zur R, Garcia-Ibanez L, Nunez-Buiza A, Aparicio N, Liappas G, Escós A, Risco A, Page A, Saiz-Ladera C, Alsina-Beauchamp D et al.. (2015) Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis. Oncotarget, 6 (15): 12920-35. [PMID:26079427]

How to cite this page

p38 subfamily: mitogen-activated protein kinase 13. Last modified on 30/06/2020. Accessed on 25/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1502.