mitogen-activated protein kinase kinase kinase kinase 4 | MSN subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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mitogen-activated protein kinase kinase kinase kinase 4

target has curated data in GtoImmuPdb

Target id: 2088

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 4

Abbreviated Name: HGK

Family: MSN 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 - 1165 2q11.2-q12 MAP4K4 mitogen-activated protein kinase kinase kinase kinase 4
Mouse - 1288 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
MAPK/ERK kinase kinase kinase 4 | MEKKK 4 | Nck-interacting kinase | NIK
Database Links
BRENDA
CATH/Gene3D
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
compound 26 [PMID: 24673130] Hs Inhibition 7.8 pIC50 5
pIC50 7.8 (IC50 1.7x10-8 M) [5]
compound 21 [PMID: 23312943] Hs Inhibition 7.7 pIC50 9
pIC50 7.7 (IC50 1.8x10-8 M) [9]
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: 6,14

Key to terms and symbols Click column headers to sort
Target used in screen: MAP4K4
Ligand Sp. Type Action Value Parameter
bosutinib Hs Inhibitor Inhibition 8.1 pKd
AST-487 Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Hs Inhibitor Inhibition 7.6 pKd
staurosporine Hs Inhibitor Inhibition 7.6 pKd
KW-2449 Hs Inhibitor Inhibition 7.5 pKd
doramapimod Hs Inhibitor Inhibition 7.1 pKd
A-674563 Hs Inhibitor Inhibition 6.8 pKd
sunitinib Hs Inhibitor Inhibition 6.8 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.8 pKd
dovitinib 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
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

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 Hs Inhibitor Inhibition 0.1
Gö 6976 Hs Inhibitor Inhibition 0.4
JAK3 inhibitor VI Hs Inhibitor Inhibition 0.6
bosutinib Hs Inhibitor Inhibition 1.0
SB 218078 Hs Inhibitor Inhibition 1.0
staurosporine Hs Inhibitor Inhibition 1.9
dovitinib Hs Inhibitor Inhibition 3.0
SU11652 Hs Inhibitor Inhibition 4.3
alsterpaullone Hs Inhibitor Inhibition 4.5
PKR inhibitor, negative control 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) [7,11-12]. 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:  10
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
References:  10
Physiological Consequences of Altering Gene Expression
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:  16
Conditional knockout of hgk in mouse T cells induces spontaneous development of systemic inflammation and type 2 diabetes.
Species:  Mouse
Tissue: 
Technique: 
References:  4
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:  13
General Comments
In vitro analyses suggest that HGK is involved in promoting cell transformation or migration in cancers [8,15], and in the regulation of adipogenesis and TNFα-induced insulin resistance in pancreatic β cells [2-3].

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. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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 06/06/2018. Accessed on 18/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2088.