mitogen-activated protein kinase kinase kinase kinase 5 | KHS subfamily | IUPHAR/BPS Guide to PHARMACOLOGY

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mitogen-activated protein kinase kinase kinase kinase 5

target has curated data in GtoImmuPdb

Target id: 2089

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 5

Abbreviated Name: KHS1

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 - 864 14q11.2-q21 MAP4K5 mitogen-activated protein kinase kinase kinase kinase 5
Mouse - 847 12 C3 Map4k5 mitogen-activated protein kinase kinase kinase kinase 5
Rat - 846 6 q24 Map4k5 mitogen-activated protein kinase kinase kinase kinase 5
Previous and Unofficial Names
KHS | KHS1 | MAPKKKK5
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
NIK SMI1 Hs Inhibition 7.3 pKi 2
pKi 7.3 (Ki 4.96x10-8 M) [2]
bosutinib Hs Inhibition 9.5 pIC50 6
pIC50 9.5 (IC50 3x10-10 M) [6]
RIPK1 inhibitor 22b Hs Inhibition 7.4 pIC50 5
pIC50 7.4 (IC50 3.7x10-8 M) [5]
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: 4,10

Key to terms and symbols Click column headers to sort
Target used in screen: MAP4K5
Ligand Sp. Type Action Value Parameter
bosutinib Hs Inhibitor Inhibition 9.3 pKd
neratinib Hs Inhibitor Inhibition 9.2 pKd
foretinib Hs Inhibitor Inhibition 8.4 pKd
staurosporine Hs Inhibitor Inhibition 7.7 pKd
sunitinib Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Hs Inhibitor Inhibition 7.4 pKd
dasatinib Hs Inhibitor Inhibition 7.3 pKd
crizotinib Hs Inhibitor Inhibition 7.1 pKd
PHA-665752 Hs Inhibitor Inhibition 7.1 pKd
tozasertib Hs Inhibitor Inhibition 7.1 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/KHS(MAP4K5)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 0.5
SU11652 Hs Inhibitor Inhibition 0.8
K-252a Hs Inhibitor Inhibition 1.1
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 1.7
bosutinib Hs Inhibitor Inhibition 1.7
SB 218078 Hs Inhibitor Inhibition 2.7
SU6656 Hs Inhibitor Inhibition 3.1
dasatinib Hs Inhibitor Inhibition 3.1
dovitinib Hs Inhibitor Inhibition 3.3
sunitinib Hs Inhibitor Inhibition 4.1
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The kinase activity of KHS (KHS1; MAP4K5) is potently induced by TNFα in lymphocyte cell lines such as Jurkat T cells and HS-Sultan B cells [8-9], and in primary B cells [3]. JNK activation by KHS is dependent on kinase activity [8], and on the presence of the downstream pathway kinases the MAP3K, MEKK1 (MAP3K1), and the MAP2K, MKK4 (MAP2K4) [3]. In B cells KHS is implicated in Wnt-induced Rac-JNK signalling [7].
The in vivo functions of KHS in the immune system remain unclear. Hypothetically, it may be involved via JNK activation, in TNFα-associated inflammatory responses, e.g. autoimmune inflammation, obesity, and type 2 diabetes. KHS may also regulate adaptive immune responses via its role in regulating CD40 signalling. And Wnt signalling is important for B cell and T cell development and differentiation.

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. Brightbill HD, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol EB, Castanedo GM, Jackson BT, Kwon YC, Haller S et al.. (2018) NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat Commun, 9 (1): 179. [PMID:29330524]

3. Chin AI, Shu J, Shan Shi C, Yao Z, Kehrl JH, Cheng G. (1999) TANK potentiates tumor necrosis factor receptor-associated factor-mediated c-Jun N-terminal kinase/stress-activated protein kinase activation through the germinal center kinase pathway. Mol. Cell. Biol., 19 (10): 6665-72. [PMID:10490605]

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. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J. Med. Chem., 61 (24): 11398-11414. [PMID:30480444]

6. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M et al.. (2009) Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia, 23 (3): 477-85. [PMID:19039322]

7. Shi CS, Huang NN, Harrison K, Han SB, Kehrl JH. (2006) The mitogen-activated protein kinase kinase kinase kinase GCKR positively regulates canonical and noncanonical Wnt signaling in B lymphocytes. Mol. Cell. Biol., 26 (17): 6511-21. [PMID:16914735]

8. 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]

9. Shi CS, Leonardi A, Kyriakis J, Siebenlist U, Kehrl JH. (1999) TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related. J. Immunol., 163 (6): 3279-85. [PMID:10477597]

10. 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 5. Last modified on 11/12/2018. Accessed on 16/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2089.