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protein tyrosine kinase 2 beta

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2181

Nomenclature: protein tyrosine kinase 2 beta

Abbreviated Name: Pyk2

Family: Fak family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1009 8p21.2 PTK2B protein tyrosine kinase 2 beta
Mouse - 1009 14 34.36 cM Ptk2b PTK2 protein tyrosine kinase 2 beta
Rat - 1009 15p12 Ptk2b protein tyrosine kinase 2 beta
Previous and Unofficial Names Click here for help
CADTK | CAK beta | CAKB | calcium-dependent tyrosine kinase | cell adhesion kinase beta | FADK 2 | focal adhesion kinase 2 | RAFTK | related adhesion focal tyrosine kinase | proline-rich tyrosine kinase 2
Database Links Click here for help
Alphafold Q14289 (Hs), Q9QVP9 (Mm), P70600 (Rn)
BRENDA 2.7.10.2
CATH/Gene3D 1.20.80.10
ChEMBL Target CHEMBL5469 (Hs), CHEMBL1075289 (Mm), CHEMBL1075222 (Rn)
Ensembl Gene ENSG00000120899 (Hs), ENSMUSG00000059456 (Mm), ENSRNOG00000027839 (Rn)
Entrez Gene 2185 (Hs), 19229 (Mm), 50646 (Rn)
Human Protein Atlas ENSG00000120899 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:2185 (Hs), mmu:19229 (Mm), rno:50646 (Rn)
OMIM 601212 (Hs)
Pharos Q14289 (Hs)
RefSeq Nucleotide NM_004103 (Hs), NM_001162365 (Mm), NM_017318 (Rn)
RefSeq Protein NP_004094 (Hs), NP_001155837 (Mm), NP_059014 (Rn)
UniProtKB Q14289 (Hs), Q9QVP9 (Mm), P70600 (Rn)
Wikipedia PTK2B (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of kinase domain of protein tyrosine kinase 2 beta (PTK2B)
PDB Id:  3CC6
Resolution:  1.6Å
Species:  Human
References: 
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of PYK2 with the indole 10c
PDB Id:  4H1M
Resolution:  1.99Å
Species:  Human
References:  3
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
aloisine Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.0 pKi 2
⤷ pKi 6.0 (Ki 9.33x10-7 M) [2]
NVP-TAE 226 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 – 8.7 pIC50 11
⤷ pIC50 8.3 – 8.7 (IC50 5x10-9 – 2x10-9 M) [11]
PF-562271 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.9 pIC50 13
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [13]
conteltinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >7.7 pIC50 15
⤷ pIC50 >7.7 (IC50 <2x10-8 M) [15]
Description: In a time-resolved fluorescence (TRF) assay using recombinant GST-tagged Pyk2.
Inhibitor Comments
PF-562271 inhibits FAK in a cell-based assay with an IC50 of 5nM [13].
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: 7,14
Key to terms and symbols Click column headers to sort
Target used in screen: PYK2
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.0 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
BI-2536 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 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: 1,8
Key to terms and symbols Click column headers to sort
Target used in screen: Pyk2/PYK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.7 1.5 0.5
K-252a Small molecule or natural product Hs Inhibitor Inhibition 17.0 3.0 -1.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 26.7 4.0 4.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 30.5 7.0 2.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 30.5 15.0 3.0
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 32.6
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 33.6 4.0 1.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 38.3
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 41.5 90.0 107.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 43.1 22.0 5.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
FAK and Pyk2 are phosphorylated downstream of the T cell antigen receptor (TCR) to bring about receptor-specific (e.g. chemokine and integrin receptors) T cell development and activation [5].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Immuno Process:  T cell (activation)
Tissue Distribution Click here for help
PYK2 expression is relatively restricted with highest levels in brain and the hematopoeitic system.
Species:  Human
Technique: 
References:  10
Physiological Functions Click here for help
Pyk2 enzyme is essential for inflammasome adaptor protein ASC phosphorylation and oligomerization necessary for NLRP3 inflammasome activation.
Species:  Human
Tissue:  Human monocyte-derived macrophages.
References:  6
Physiological Consequences of Altering Gene Expression Click here for help
Pyk2(-/-) micedevelop normally, but show defects in their innume system: they have no marginal zone B-cells, abnormal T-cell independent type II responses, and altered macrophage morphology, migration and signaling in response to cell attachment or chemokine treatment.
Species:  Mouse
Tissue:  Immune system
Technique: 
References:  9,12
Pyk2(-/-) mice have increased susceptibility to diet-induced obesity and diabetes.
Species:  Mouse
Tissue: 
Technique: 
References:  16
Pyk2(-/-) mice exhibit a high bone mass phenotype resulting from increased osteogenesis and osteoblast activity
Species:  Mouse
Tissue: 
Technique: 
References:  4

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. Anderson PC, De Sapio V, Turner KB, Elmer SP, Roe DC, Schoeniger JS. (2012) Identification of binding specificity-determining features in protein families. J Med Chem, 55 (5): 1926-39. [PMID:22289061]

3. Bhattacharya SK, Aspnes GE, Bagley SW, Boehm M, Brosius AD, Buckbinder L, Chang JS, Dibrino J, Eng H, Frederick KS et al.. (2012) Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors. Bioorg Med Chem Lett, 22 (24): 7523-9. [PMID:23153798]

4. Buckbinder L, Crawford DT, Qi H, Ke HZ, Olson LM, Long KR, Bonnette PC, Baumann AP, Hambor JE, Grasser 3rd WA et al.. (2007) Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci USA, 104 (25): 10619-24. [PMID:17537919]

5. Chapman NM, Houtman JC. (2014) Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. Immunol Res, 59 (1-3): 23-34. [PMID:24816556]

6. Chung IC, OuYang CN, Yuan SN, Li HP, Chen JT, Shieh HR, Chen YJ, Ojcius DM, Chu CL, Yu JS et al.. (2016) Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis. Sci Rep, 6: 36214. [PMID:27796369]

7. 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]

8. 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]

9. Guinamard R, Okigaki M, Schlessinger J, Ravetch JV. (2000) Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat Immunol, 1 (1): 31-6. [PMID:10881171]

10. Han S, Mistry A, Chang JS, Cunningham D, Griffor M, Bonnette PC, Wang H, Chrunyk BA, Aspnes GE, Walker DP et al.. (2009) Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. J Biol Chem, 284 (19): 13193-201. [PMID:19244237]

11. Liu TJ, LaFortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T, Jackson D, de Groot J, Yung WK. (2007) Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther, 6 (4): 1357-67. [PMID:17431114]

12. Okigaki M, Davis C, Falasca M, Harroch S, Felsenfeld DP, Sheetz MP, Schlessinger J. (2003) Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci USA, 100 (19): 10740-5. [PMID:12960403]

13. Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J et al.. (2008) Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res, 68 (6): 1935-44. [PMID:18339875]

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. Xiao D, Cheng L, Liu X, Hu Y, Xu X, Liu Z, Zhang L, Wu W, Wang S, Shen Y et al.. (2012) 2,4-DIAMINO-6,7-DIHYDRO-5H-PYRROLO[2,3]PYRIMIDINE DERIVATIVES AS FAK/Pyk2 INHIBITORS. Patent number: WO2012092880. Assignee: Centaurus Biopharma Co., Ltd.. Priority date: 07/01/2011. Publication date: 12/07/2012.

16. Yu Y, Ross SA, Halseth AE, Hollenbach PW, Hill RJ, Gulve EA, Bond BR. (2005) Role of PYK2 in the development of obesity and insulin resistance. Biochem Biophys Res Commun, 334 (4): 1085-91. [PMID:16039993]

How to cite this page

Fak family: protein tyrosine kinase 2 beta. Last modified on 23/01/2018. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2181.