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Target has curated data in GtoImmuPdb
Target id: 2086
Nomenclature: mitogen-activated protein kinase kinase kinase kinase 2
Abbreviated Name: GCK
Family: KHS subfamily
Gene and Protein Information | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | - | 820 | 11q13.1 | MAP4K2 | mitogen-activated protein kinase kinase kinase kinase 2 | |
Mouse | - | 821 | 19 A | Map4k2 | mitogen-activated protein kinase kinase kinase kinase 2 | |
Rat | - | 780 | 1 q43 | Map4k2 | mitogen activated protein kinase kinase kinase kinase 2 |
Previous and Unofficial Names |
Germinal center kinase | Rab8-interacting protein | RAB8IP | B lymphocyte serine/threonine-protein kinase | MAPK/ERK kinase kinase kinase 2 | MEKKK 2 |
Database Links | |
Alphafold | Q12851 (Hs), Q61161 (Mm) |
BRENDA | 2.7.11.1 |
ChEMBL Target | CHEMBL5330 (Hs), CHEMBL4295856 (Mm) |
Ensembl Gene | ENSG00000168067 (Hs), ENSMUSG00000024948 (Mm), ENSRNOG00000021061 (Rn) |
Entrez Gene | 5871 (Hs), 26412 (Mm), 293694 (Rn) |
Human Protein Atlas | ENSG00000168067 (Hs) |
KEGG Enzyme | 2.7.11.1 |
KEGG Gene | hsa:5871 (Hs), mmu:26412 (Mm), rno:293694 (Rn) |
OMIM | 603166 (Hs) |
Pharos | Q12851 (Hs) |
RefSeq Nucleotide | NM_004579 (Hs), NM_009006 (Mm), NM_001106329 (Rn) |
RefSeq Protein | NP_004570 (Hs), NP_033032 (Mm), NP_001099799 (Rn) |
UniProtKB | Q12851 (Hs), Q61161 (Mm) |
Wikipedia | MAP4K2 (Hs) |
Enzyme Reaction | ||||
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Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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DiscoveRx KINOMEscan® screen | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: 4,12 |
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Target used in screen: MAP4K2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Displaying the top 10 most potent ligands View all ligands in screen » |
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: 1,5 |
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Target used in screen: GCK/GCK(MAP4K2) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Displaying the top 10 most potent ligands View all ligands in screen » |
Immunopharmacology Comments |
In vitro analyses suggest that GCK plays important roles in the innate immune response and cell signalling [3]. GCK kinase activity is potently induced by TNFα, IL-1, CD-40 ligand and some TLR ligands (lipid A, poly(I:C), LPS) [14]. The in vivo roles of GCK in immune regulation remain unclear. GCK selectively activates the JNK signalling pathway, and has no effect on the NF-κB, p38 or ERK pathways in vitro. JNK pathway stimulation is mediated by GCK activation of the MAP3K, MEKK1 (MAP3K1), via a mechanism of MEKK1 oligomerization and autophosphorylation that is independent of GCK kinase activity [2]. In addition, the E3-ligase activity of TRAF2 is required for MEKK1 activation by GCK. GCK activation of MLK3 (MAP3K11) and downstream JNK activity does require kinase activity [2]. |
Cell Type Associations | ||||||||
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Immuno Process Associations | ||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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Physiological Consequences of Altering Gene Expression Comments | ||||||||||
Note that the article reporting gck knockout effects in mice [13] was later retracted in its entirety, as many of the experimental findings were unreproducible when the gck-/- mouse line was rederived [6]. |
1. 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]
2. Chadee DN, Yuasa T, Kyriakis JM. (2002) Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol, 22 (3): 737-49. [PMID:11784851]
3. Chuang HC, Wang X, Tan TH. (2016) MAP4K Family Kinases in Immunity and Inflammation. Adv Immunol, 129: 277-314. [PMID:26791862]
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. 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]
6. Gavrilescu LC, Molnár Á, Murray L, Garafalo S, Kehrl JH, Simon AR, Van Etten RA, Kyriakis JM. (2012) Retraction for Zhong et al. GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38. Proc Natl Acad Sci USA, 109 (13): 5134. [PMID:22411792]
7. Himes SR, Sester DP, Ravasi T, Cronau SL, Sasmono T, Hume DA. (2006) The JNK are important for development and survival of macrophages. J Immunol, 176 (4): 2219-28. [PMID:16455978]
8. Katz P, Whalen G, Kehrl JH. (1994) Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center. J Biol Chem, 269 (24): 16802-9. [PMID:7515885]
9. Lau KS, Zhang T, Kendall KR, Lauffenburger D, Gray NS, Haigis KM. (2012) BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner. PLoS ONE, 7 (7): e41343. [PMID:22815993]
10. Lewis RT, Bode CM, Choquette DM, Potashman M, Romero K, Stellwagen JC, Teffera Y, Moore E, Whittington DA, Chen H et al.. (2012) The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer. J Med Chem, 55 (14): 6523-40. [PMID:22734674]
11. Tan L, Nomanbhoy T, Gurbani D, Patricelli M, Hunter J, Geng J, Herhaus L, Zhang J, Pauls E, Ham Y et al.. (2015) Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2). J Med Chem, 58 (1): 183-96. [PMID:25075558]
12. 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]
13. Zhong J, Gavrilescu LC, Molnár A, Murray L, Garafalo S, Kehrl JH, Simon AR, Van Etten RA, Kyriakis JM. (2009) GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38. Proc Natl Acad Sci USA, 106 (11): 4372-7. [PMID:19246396]
14. Zhong J, Kyriakis JM. (2004) Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization. Mol Cell Biol, 24 (20): 9165-75. [PMID:15456887]
KHS subfamily: mitogen-activated protein kinase kinase kinase kinase 2. Last modified on 04/09/2019. Accessed on 04/11/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2086.