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target has curated data in GtoImmuPdb
Target id: 2088
Nomenclature: mitogen-activated protein kinase kinase kinase kinase 4
Abbreviated Name: HGK
Family: MSN subfamily
Gene and Protein Information | ||||||
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 |
MAPK/ERK kinase kinase kinase 4 | MEKKK 4 | Nck-interacting kinase | NIK |
Database Links | |
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 | ||||
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 8,17 |
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Target used in screen: MAP4K4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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: ...2 |
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Target used in screen: nd/HGK(MAP4K4) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | ||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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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]. |
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]
MSN subfamily: mitogen-activated protein kinase kinase kinase kinase 4. Last modified on 19/03/2024. Accessed on 09/11/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2088.