mitogen-activated protein kinase kinase kinase kinase 3 | KHS subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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mitogen-activated protein kinase kinase kinase kinase 3

  Target has curated data in GtoImmuPdb

Target id: 2087

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 3

Abbreviated Name: KHS2

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 - 894 2p22.3 MAP4K3 mitogen-activated protein kinase kinase kinase kinase 3
Mouse - 894 17 E3 Map4k3 mitogen-activated protein kinase kinase kinase kinase 3
Rat - 873 6 q11 Map4k3 mitogen-activated protein kinase kinase kinase kinase 3
Previous and Unofficial Names
GLK | MAPK/ERK kinase kinase kinase 3 | MAPKKKK3 | MEKKK 3 | RAB8IPL1
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
RIPK3 inhibitor 18 Hs Inhibition 7.9 pIC50 6
pIC50 7.9 (IC50 1.2x10-8 M) [6]
compound 8h [PMID: 22765894] Hs Inhibition 7.6 pIC50 7
pIC50 7.6 (IC50 2.5x10-8 M) [7]
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: 4,8

Key to terms and symbols Click column headers to sort
Target used in screen: MAP4K3
Ligand Sp. Type Action Value Parameter
bosutinib Hs Inhibitor Inhibition 8.3 pKd
neratinib Hs Inhibitor Inhibition 8.1 pKd
staurosporine Hs Inhibitor Inhibition 8.1 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.2 pKd
crizotinib Hs Inhibitor Inhibition 7.1 pKd
lestaurtinib Hs Inhibitor Inhibition 7.0 pKd
foretinib Hs Inhibitor Inhibition 7.0 pKd
midostaurin Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Hs Inhibitor Inhibition 6.8 pKd
sunitinib Hs Inhibitor Inhibition 6.7 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
GLK (KHS2; MAP4K3) is ubiquitously expressed. It is involved in cellular responses to stress and inflammation [5], and is important for generating a protective immune memory against pathogens. GLK activates JNK (via MEKK1/MAP3K1), and NF-κB signalling in antigen-engaged T cells (via a SLP-76-dependent mechanism) [3].
GLK expression is elevated in T cells isolated from patients with autoimmune diseases, including SLE [3], adult-onset Still's disease [1] and rheumatoid arthritis [2], and given that numbers of GLK-expressing T cells correlate with disease severity in these conditions, it is likely that GLK overexpression and activation of downstream signalling pathways contributes to the pathogenesis of autoimmune diseases.
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0034612 response to tumor necrosis factor IDA
Physiological Consequences of Altering Gene Expression
MIce deficient for glk show a phenotype which is opposite to that of hpk1 knockout mice, i.e. glk-deficiency produces mice with impaired T cell activation, reduced cytokine production, decreased antibody production after KLH immunization, and which are resistant to experimental autoimmune encephalomyelitis induction.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells.
References:  3
Gene Expression and Pathophysiology
GLK expression is enhanced in patients with systemic lupus erythematosus.
Tissue or cell type: 
Pathophysiology: 
Species:  Human
Technique: 
References:  3

References

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1. Chen DY, Chuang HC, Lan JL, Chen YM, Hung WT, Lai KL, Tan TH. (2012) Germinal center kinase-like kinase (GLK/MAP4K3) expression is increased in adult-onset Still's disease and may act as an activity marker. BMC Med, 10: 84. [PMID:22867055]

2. Chen YM, Chuang HC, Lin WC, Tsai CY, Wu CW, Gong NR, Hung WT, Lan TH, Lan JL, Tan TH et al.. (2013) Germinal center kinase-like kinase overexpression in T cells as a novel biomarker in rheumatoid arthritis. Arthritis Rheum., 65 (10): 2573-82. [PMID:23817999]

3. Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP, Huang CY, Liu PE, Wang X, Tan TH. (2011) The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells. Nat. Immunol., 12 (11): 1113-8. [PMID:21983831]

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. Diener K, Wang XS, Chen C, Meyer CF, Keesler G, Zukowski M, Tan TH, Yao Z. (1997) Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc. Natl. Acad. Sci. U.S.A., 94 (18): 9687-92. [PMID:9275185]

6. Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ et al.. (2019) Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. ACS Medicinal Chemistry Letters, Article ASAP. DOI: 10.1021/acsmedchemlett.9b00065

7. Kim MH, Tsuhako AL, Co EW, Aftab DT, Bentzien F, Chen J, Cheng W, Engst S, Goon L, Klein RR et al.. (2012) The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 22 (15): 4979-85. [PMID:22765894]

8. 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]

How to cite this page

KHS subfamily: mitogen-activated protein kinase kinase kinase kinase 3. Last modified on 17/05/2019. Accessed on 19/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2087.