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mitogen-activated protein kinase kinase kinase kinase 4

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2088

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 4

Abbreviated Name: HGK

Family: MSN subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1239 2q11.2 MAP4K4 mitogen-activated protein kinase kinase kinase kinase 4
Mouse - 1233 1 B Map4k4 mitogen-activated protein kinase kinase kinase kinase 4
Rat - 1178 9 q21 Map4k4 mitogen-activated protein kinase kinase kinase kinase 4
Previous and Unofficial Names Click here for help
MAPK/ERK kinase kinase kinase 4 | MEKKK 4 | Nck-interacting kinase | NIK
Database Links Click here for help
Alphafold O95819 (Hs), P97820 (Mm)
BRENDA 2.7.11.1
CATH/Gene3D 2.130.10.10
ChEMBL Target CHEMBL6166 (Hs)
Ensembl Gene ENSG00000071054 (Hs), ENSMUSG00000026074 (Mm), ENSRNOG00000014013 (Rn)
Entrez Gene 9448 (Hs), 26921 (Mm), 301363 (Rn)
Human Protein Atlas ENSG00000071054 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:9448 (Hs), mmu:26921 (Mm), rno:301363 (Rn)
OMIM 604666 (Hs)
Pharos O95819 (Hs)
RefSeq Nucleotide NM_001242559 (Hs), NM_001252200 (Mm), NM_001106904 (Rn)
RefSeq Protein NP_004825 (Hs), NP_001239129 (Mm), NP_001100374 (Rn)
UniProtKB O95819 (Hs), P97820 (Mm)
Wikipedia MAP4K4 (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
compound 12k [PMID: 31676236] Small molecule or natural product Hs Inhibition 9.5 pIC50 3
⤷ pIC50 9.5 (IC50 3x10-10 M) [3]
Description: Inhibition of HGK activity in cell-free radiolabeled ATP assay
PF06260933 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 1,10
⤷ pIC50 8.4 (IC50 3.7x10-9 M) [1,10]
Description: Inhibition of recombinant human MAP4K4 catalytic domain, determined in a FRET assay
compound 26 [PMID: 24673130] Small molecule or natural product Primary target of this compound Hs Inhibition 7.8 pIC50 7
⤷ pIC50 7.8 (IC50 1.7x10-8 M) [7]
compound 21 [PMID: 23312943] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 12
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [12]
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: 8,17
Key to terms and symbols Click column headers to sort
Target used in screen: MAP4K4
Ligand Sp. Type Action Value Parameter
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.1 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.5 pKd
doramapimod Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.8 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
Key to terms and symbols Click column headers to sort
Target used in screen: nd/HGK(MAP4K4)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 0.1
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.4
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 0.6
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 1.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 1.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.9
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 3.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.3
PKR inhibitor, negative control Small molecule or natural product Hs Inhibitor Inhibition 4.5
alsterpaullone Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.5
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
HGK is widely expressed in different tissues. In vitro, HGK is activated by TNFα stimulation, and this results in JNK activation via the MAP3K, TAK1 (MAP3K7) and the MAP2Ks, MKK4 (MAP2K4) and MKK7 (MAP2K7) [9,14-15]. HGK is important for regulating innate immune responses, in part by being involved in maintaining the resting state of T cells.
Cell Type Associations
Immuno Cell Type:  T cells
References:  13
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
References:  13
Physiological Consequences of Altering Gene Expression Click here for help
Whole body hgk knockout in mice is embryonic lethal. Nik-/- mice die postgastrulation between embryonic day (E) 9.5 and E10.5, indicating that hgk is required for mesodermal and somite development.
Species:  Mouse
Tissue: 
Technique: 
References:  19
Conditional knockout of hgk in mouse T cells induces spontaneous development of systemic inflammation and type 2 diabetes.
Species:  Mouse
Tissue: 
Technique: 
References:  6
Conditional knockout (cKO) of HGK in endothelial cells shows that this kinase is involved in the control of endothelial cell motility. Heterozygous cKO mice show no defects, but homozygous cKO is embryonic lethal.
Species:  Mouse
Tissue: 
Technique:  A floxed allele of Map4k4 crossed to Tie2-Cre mice to induce endothelial cell conditional knockout mouse line.
References:  16
General Comments
In vitro analyses suggest that HGK is involved in promoting cell transformation or migration in cancers [11,18], and in the regulation of adipogenesis and TNFα-induced insulin resistance in pancreatic β cells [4-5].

References

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1. Ammirati M, Bagley SW, Bhattacharya SK, Buckbinder L, Carlo AA, Conrad R, Cortes C, Dow RL, Dowling MS, El-Kattan A et al.. (2015) Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment. ACS Med Chem Lett, 6 (11): 1128-33. [PMID:26617966]

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. Bos PH, Lowry ER, Costa J, Thams S, Garcia-Diaz A, Zask A, Wichterle H, Stockwell BR. (2019) Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents. Cell Chem Biol, 26 (12): 1703-1715.e37. [PMID:31676236]

4. Bouzakri K, Ribaux P, Halban PA. (2009) Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion. J Biol Chem, 284 (41): 27892-8. [PMID:19690174]

5. Bouzakri K, Zierath JR. (2007) MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance. J Biol Chem, 282 (11): 7783-9. [PMID:17227768]

6. Chuang HC, Sheu WH, Lin YT, Tsai CY, Yang CY, Cheng YJ, Huang PY, Li JP, Chiu LL, Wang X et al.. (2014) HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance. Nat Commun, 5: 4602. [PMID:25098764]

7. Crawford TD, Ndubaku CO, Chen H, Boggs JW, Bravo BJ, Delatorre K, Giannetti AM, Gould SE, Harris SF, Magnuson SR et al.. (2014) Discovery of selective 4-Amino-pyridopyrimidine inhibitors of MAP4K4 using fragment-based lead identification and optimization. J Med Chem, 57 (8): 3484-93. [PMID:24673130]

8. 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]

9. 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]

10. Dow RL, Ammirati M, Bagley SW, Bhattacharya SK, Buckbinder L, Cortes C, El-Kattan AF, Ford K, Freeman GB, Guimarães CRW et al.. (2018) 2-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based Safety. J Med Chem, 61 (7): 3114-3125. [PMID:29570292]

11. Liang JJ, Wang H, Rashid A, Tan TH, Hwang RF, Hamilton SR, Abbruzzese JL, Evans DB, Wang H. (2008) Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Clin Cancer Res, 14 (21): 7043-9. [PMID:18981001]

12. Powell NA, Hoffman JK, Ciske FL, Kohrt JT, Baxi SM, Peng YW, Zhong M, Catana C, Ohren J, Perrin LA et al.. (2013) Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. Bioorg Med Chem Lett, 23 (4): 1051-5. [PMID:23312943]

13. Shi CS, Kehrl JH. (1997) Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2- and germinal center kinase related-dependent pathway. J Biol Chem, 272 (51): 32102-7. [PMID:9405407]

14. Su YC, Han J, Xu S, Cobb M, Skolnik EY. (1997) NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J, 16 (6): 1279-90. [PMID:9135144]

15. Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Machida N, Uezato H, Nonaka S, Kariya K. (2004) The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. J Biol Chem, 279 (47): 49488-96. [PMID:15342639]

16. Vitorino P, Yeung S, Crow A, Bakke J, Smyczek T, West K, McNamara E, Eastham-Anderson J, Gould S, Harris SF et al.. (2015) MAP4K4 regulates integrin-FERM binding to control endothelial cell motility. Nature, 519 (7544): 425-30. [PMID:25799996]

17. 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]

18. Wright JH, Wang X, Manning G, LaMere BJ, Le P, Zhu S, Khatry D, Flanagan PM, Buckley SD, Whyte DB et al.. (2003) The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion. Mol Cell Biol, 23 (6): 2068-82. [PMID:12612079]

19. Xue Y, Wang X, Li Z, Gotoh N, Chapman D, Skolnik EY. (2001) Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK). Development, 128 (9): 1559-72. [PMID:11290295]

How to cite this page

MSN subfamily: mitogen-activated protein kinase kinase kinase kinase 4. Last modified on 19/03/2024. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2088.