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mitogen-activated protein kinase kinase kinase kinase 3

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2087

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 3

Abbreviated Name: KHS2

Family: KHS subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 894 2p22.1 MAP4K3 mitogen-activated protein kinase kinase kinase kinase 3
Mouse - 894 17 E3 Map4k3 mitogen-activated protein kinase kinase kinase kinase 3
Rat - 873 6q11 Map4k3 mitogen-activated protein kinase kinase kinase kinase 3
Previous and Unofficial Names Click here for help
GLK | MAPK/ERK kinase kinase kinase 3 | MAPKKKK3 | MEKKK 3 | RAB8IPL1
Database Links Click here for help
Alphafold Q8IVH8 (Hs), Q99JP0 (Mm), Q924I2 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL5432 (Hs)
Ensembl Gene ENSG00000011566 (Hs), ENSMUSG00000024242 (Mm), ENSRNOG00000007172 (Rn)
Entrez Gene 8491 (Hs), 225028 (Mm), 170920 (Rn)
Human Protein Atlas ENSG00000011566 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:8491 (Hs), mmu:225028 (Mm), rno:170920 (Rn)
OMIM 604921 (Hs)
Pharos Q8IVH8 (Hs)
RefSeq Nucleotide NM_001270425 (Hs), NM_001290345 (Mm), NM_133407 (Rn)
RefSeq Protein NP_003609 (Hs), NP_001277274 (Mm), NP_596898 (Rn)
UniProtKB Q8IVH8 (Hs), Q99JP0 (Mm), Q924I2 (Rn)
Wikipedia MAP4K3 (Hs)
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

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
RIPK3 inhibitor 18 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.9 pIC50 6
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [6]
compound 8h [PMID: 22765894] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 7
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [7]
compound 5i [PMID: 36542759] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.1 pIC50 8
⤷ pIC50 7.1 (IC50 8.1x10-8 M) [8]
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: 4,9
Key to terms and symbols Click column headers to sort
Target used in screen: MAP4K3
Ligand Sp. Type Action Value Parameter
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.3 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 8.1 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.1 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.0 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.9 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure 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
Physiological Consequences of Altering Gene Expression Click here for help
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 Click here for help
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 USA, 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 Med Chem Lett, 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. Wang MS, Wang ZZ, Li ZL, Gong Y, Duan CX, Cheng QH, Huang W, Yang GF. (2023) Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy. J Med Chem, 66 (1): 611-626. [PMID:36542759]

9. 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 25/01/2023. Accessed on 16/01/2025. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2087.