mitogen-activated protein kinase kinase kinase kinase 2 | KHS subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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mitogen-activated protein kinase kinase kinase kinase 2

  Target has curated data in GtoImmuPdb

Target id: 2086

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 2

Abbreviated Name: GCK

Family: KHS subfamily

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

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
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.11.1

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
Ligand Sp. Action Value Parameter Reference
belizatinib Hs Inhibition 8.0 pKd 10
pKd 8.0 (Kd 1.1x10-8 M) [10]
Description: Binding affinity in vitro.
BAY 61-3606 Hs Inhibition 7.9 pIC50 9
pIC50 7.9 (IC50 1.13x10-8 M) [9]
NG-25 Hs Inhibition 7.7 pIC50 11
pIC50 7.7 (IC50 2.17x10-8 M) [11]
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

Key to terms and symbols Click column headers to sort
Target used in screen: MAP4K2
Ligand Sp. Type Action Value Parameter
bosutinib Hs Inhibitor Inhibition 8.5 pKd
lestaurtinib Hs Inhibitor Inhibition 8.3 pKd
staurosporine Hs Inhibitor Inhibition 8.1 pKd
KW-2449 Hs Inhibitor Inhibition 8.0 pKd
sunitinib Hs Inhibitor Inhibition 7.5 pKd
JNJ-28312141 Hs Inhibitor Inhibition 7.2 pKd
crizotinib Hs Inhibitor Inhibition 7.1 pKd
alvocidib Hs Inhibitor Inhibition 7.1 pKd
PP-242 Hs Inhibitor Inhibition 7.0 pKd
AST-487 Hs Inhibitor Inhibition 7.0 pKd
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

Key to terms and symbols Click column headers to sort
Target used in screen: GCK/GCK(MAP4K2)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 0.5 -1.0 1.5
K-252a Hs Inhibitor Inhibition 0.8 0.0 1.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 2.1 1.0 -1.0
bosutinib Hs Inhibitor Inhibition 3.2
SB 218078 Hs Inhibitor Inhibition 3.7 20.0 10.0
JAK3 inhibitor VI Hs Inhibitor Inhibition 4.8 3.0 0.0
midostaurin Hs Inhibitor Inhibition 5.2 4.0 0.0
Gö 6976 Hs Inhibitor Inhibition 5.7 2.0 1.0
SU11652 Hs Inhibitor Inhibition 8.1 5.0 0.0
alsterpaullone Hs Inhibitor Inhibition 8.8 2.0 5.0
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
Immuno Cell Type:  B cells
Cell Ontology Term:   germinal center B cell (CL:0000844)
Comment:  Expression of GCK in lymphoid follicles is restricted to germinal center B cells.
References:  8
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
Comment:  GCK expression is upregulated in LPS-stimulated macrophages.
References:  7
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0045087 innate immune response IEA
Physiological Consequences of Altering Gene Expression
C57/BL6 gck−/− mice are viable and fertile, with no obvious unevoked phenotype. Their lymphoid and myeloid development appears normal.
Species:  Mouse
Tissue: 
Technique:  Homologous recombination.
References:  13
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].

References

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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. U.S.A., 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. U.S.A., 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]

How to cite this page

KHS subfamily: mitogen-activated protein kinase kinase kinase kinase 2. Last modified on 04/09/2019. Accessed on 12/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2086.