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C-terminal Src kinase

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Target id: 1994

Nomenclature: C-terminal Src kinase

Abbreviated Name: CSK

Family: Csk family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 450 15q24.1 CSK C-terminal Src kinase
Mouse - 450 9 31.18 cM Csk c-src tyrosine kinase
Rat - 450 8q24 Csk C-terminal Src kinase
Previous and Unofficial Names Click here for help
tyrosine-protein kinase CSK | c-src tyrosine kinase | CSK, non-receptor tyrosine kinase
Database Links Click here for help
Alphafold P41240 (Hs), P41241 (Mm), P32577 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 3.30.505.10
ChEMBL Target CHEMBL2634 (Hs), CHEMBL4365 (Rn)
Ensembl Gene ENSG00000103653 (Hs), ENSMUSG00000032312 (Mm), ENSRNOG00000019374 (Rn)
Entrez Gene 1445 (Hs), 12988 (Mm), 315707 (Rn)
Human Protein Atlas ENSG00000103653 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:1445 (Hs), mmu:12988 (Mm), rno:315707 (Rn)
OMIM 124095 (Hs)
Pharos P41240 (Hs)
RefSeq Nucleotide NM_001127190 (Hs), NM_007783 (Mm), NM_001030039 (Rn)
RefSeq Protein NP_001120662 (Hs), NP_031809 (Mm), NP_001025210 (Rn)
UniProtKB P41240 (Hs), P41241 (Mm), P32577 (Rn)
Wikipedia CSK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  KINASE DOMAIN OF HUMAN C-TERMINAL SRC KINASE (CSK) IN COMPLEX WITH INHIBITOR STAUROSPORINE
PDB Id:  1BYG
Resolution:  2.4Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

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
NG-25 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 7
⤷ pIC50 7.3 (IC50 5.64x10-8 M) [7]
rivoceranib Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.3 pIC50 8
⤷ pIC50 6.3 (IC50 5.3x10-7 M) [8]
Description: Assay used apatinib mesylate (YN968D1)
PP1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 pIC50 2
⤷ pIC50 6.3 (IC50 5.2x10-7 M) [2]
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: 3,10
Key to terms and symbols Click column headers to sort
Target used in screen: CSK
Ligand Sp. Type Action Value Parameter
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.0 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.9 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.3 pKd
axitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.0 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.7 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: 1,4
Key to terms and symbols Click column headers to sort
Target used in screen: CSK/CSK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.4 0.0 -1.0
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.1
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.0 29.0 3.5
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 12.3
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 18.8 12.0 3.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 31.1 71.0 18.0
nilotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 42.4
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 43.6 79.0 21.0
PDGF receptor tyrosine kinase inhibitor IV Small molecule or natural product Hs Inhibitor Inhibition 44.9 80.0 29.0
PP1 analog II Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 46.1 82.0 20.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
CSK is an inhibitory regulator of Src family kinases, a family of protein tyrosine kinases indispensable to the initiation of signal transduction via ITAM-bearing immunoreceptors, and cytokine, growth factor, and pattern recognition receptor signalling. CSK phosphorylates an inhibitory tyrosine residue at the C terminus of Src kinases, leading to autoinhibition. CSK-induced Src kinase inhibition can also be mediated by binding to PEST family receptor tyrosine phosphatases [9], which are recognised modulators in immunity, autoimmunity, and autoinflammatory disorders.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Immuno Process:  B cell (activation)
Gene Expression and Pathophysiology Comments
An intronic CSK polymorphism (associated with increased CSK expression) is identified as a risk allele for SLE. Carriers of the risk allele show increased B-cell receptor (BCR)-mediated activation of mature B cells and a higher circulating immunoglobulin M level, compared to non-carriers [6].
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  CSK intronic polymorphism rs34933034 is a risk allele for systemic lupus erythematosus.
SNP accession:  rs34933034
References:  6

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. Bain J, McLauchlan H, Elliott M, Cohen P. (2003) The specificities of protein kinase inhibitors: an update. Biochem J, 371 (Pt 1): 199-204. [PMID:12534346]

3. 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]

4. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

5. Lamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH. (1999) Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. J Mol Biol, 285 (2): 713-25. [PMID:9878439]

6. Manjarrez-Orduño N, Marasco E, Chung SA, Katz MS, Kiridly JF, Simpfendorfer KR, Freudenberg J, Ballard DH, Nashi E, Hopkins TJ et al.. (2012) CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat Genet, 44 (11): 1227-30. [PMID:23042117]

7. Tan L, Nomanbhoy T, Gurbani D, Patricelli M, Hunter J, Geng J, Herhaus L, Zhang J, Pauls E, Ham Y et al.. (2015) Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2). J Med Chem, 58 (1): 183-96. [PMID:25075558]

8. Tian S, Quan H, Xie C, Guo H, Lü F, Xu Y, Li J, Lou L. (2011) YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci, 102 (7): 1374-80. [PMID:21443688]

9. Veillette A, Rhee I, Souza CM, Davidson D. (2009) PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders. Immunol Rev, 228 (1): 312-24. [PMID:19290936]

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

Csk family: C-terminal Src kinase. Last modified on 23/05/2017. Accessed on 15/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1994.