protein tyrosine kinase 2 beta | Fak family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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protein tyrosine kinase 2 beta

  Target has curated data in GtoImmuPdb

Target id: 2181

Nomenclature: protein tyrosine kinase 2 beta

Abbreviated Name: Pyk2

Family: Fak family

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 - 1009 8p21.1 PTK2B protein tyrosine kinase 2 beta
Mouse - 1005 14 D1 Ptk2b PTK2 protein tyrosine kinase 2 beta
Rat - 1009 15 p12 Ptk2b protein tyrosine kinase 2 beta
Previous and Unofficial Names
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
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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
EC Number: 2.7.10.2

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 Affinity Parameter Reference
aloisine Hs Inhibition 6.0 pKi 2
pKi 6.0 (Ki 9.33x10-7 M) [2]
NVP-TAE 226 Hs Inhibition 8.3 – 8.7 pIC50 11
pIC50 8.3 – 8.7 (IC50 5x10-9 – 2x10-9 M) [11]
PF-562271 Hs Inhibition 7.9 pIC50 13
pIC50 7.9 (IC50 1.3x10-8 M) [13]
conteltinib 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
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 Affinity Parameter
NVP-TAE684 Hs Inhibitor Inhibition 9.0 pKd
staurosporine Hs Inhibitor Inhibition 8.5 pKd
foretinib Hs Inhibitor Inhibition 7.8 pKd
tamatinib Hs Inhibitor Inhibition 7.5 pKd
lestaurtinib Hs Inhibitor Inhibition 7.4 pKd
GSK-1838705A Hs Inhibitor Inhibition 7.1 pKd
sunitinib Hs Inhibitor Inhibition 7.1 pKd
crizotinib Hs Inhibitor Inhibition 6.7 pKd
fedratinib Hs Inhibitor Inhibition 6.7 pKd
BI-2536 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
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 Hs Inhibitor Inhibition 2.7 1.5 0.5
K-252a Hs Inhibitor Inhibition 17.0 3.0 -1.0
Gö 6976 Hs Inhibitor Inhibition 26.7 4.0 4.0
indirubin derivative E804 Hs Inhibitor Inhibition 30.5 7.0 2.0
SU11652 Hs Inhibitor Inhibition 30.5 15.0 3.0
bosutinib Hs Inhibitor Inhibition 32.6
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 33.6 4.0 1.0
sunitinib Hs Inhibitor Inhibition 38.3
SB 218078 Hs Inhibitor Inhibition 41.5 90.0 107.0
Syk inhibitor 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
GO Annotations:  Associated to 4 GO processes
GO:0002315 marginal zone B cell differentiation ISS
GO:0010758 regulation of macrophage chemotaxis ISS
GO:0045087 innate immune response IBA
GO:2000538 positive regulation of B cell chemotaxis ISS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0002315 marginal zone B cell differentiation ISS
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 3 GO processes
GO:0010758 regulation of macrophage chemotaxis ISS
GO:0045638 negative regulation of myeloid cell differentiation IMP
GO:2000538 positive regulation of B cell chemotaxis ISS
Immuno Process:  Immune system development
GO Annotations:  Associated to 2 GO processes
GO:0002315 marginal zone B cell differentiation ISS
GO:0045638 negative regulation of myeloid cell differentiation IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 4 GO processes
GO:0033209 tumor necrosis factor-mediated signaling pathway IMP
GO:0038110 interleukin-2-mediated signaling pathway TAS
GO:0038111 interleukin-7-mediated signaling pathway TAS
GO:0070098 chemokine-mediated signaling pathway ISS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 3 GO processes
GO:0010758 regulation of macrophage chemotaxis ISS
GO:0070098 chemokine-mediated signaling pathway ISS
GO:2000538 positive regulation of B cell chemotaxis ISS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0002315 marginal zone B cell differentiation ISS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002250 adaptive immune response IEA
Tissue Distribution
PYK2 expression is relatively restricted with highest levels in brain and the hematopoeitic system.
Species:  Human
Technique: 
References:  10
Physiological Functions
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
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. U.S.A., 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. U.S.A., 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 18/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2181.