General Information of Drug Off-Target (DOT) (ID: OTGAS0I8)

DOT Name Protein-tyrosine kinase 2-beta (PTK2B)
Synonyms
EC 2.7.10.2; Calcium-dependent tyrosine kinase; CADTK; Calcium-regulated non-receptor proline-rich tyrosine kinase; Cell adhesion kinase beta; CAK-beta; CAKB; Focal adhesion kinase 2; FADK 2; Proline-rich tyrosine kinase 2; Related adhesion focal tyrosine kinase; RAFTK
Gene Name PTK2B
UniProt ID
FAK2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2LK4; 3CC6; 3ET7; 3FZO; 3FZP; 3FZR; 3FZS; 3FZT; 3GM1; 3GM2; 3GM3; 3H3C; 3U3F; 4EKU; 4H1J; 4H1M; 4R32; 4XEF; 4XEK; 4XEV; 5TO8; 5TOB; 6LF3; 7PLL
EC Number
2.7.10.2
Pfam ID
PF21477 ; PF00373 ; PF18038 ; PF03623 ; PF07714
Sequence
MSGVSEPLSRVKLGTLRRPEGPAEPMVVVPVDVEKEDVRILKVCFYSNSFNPGKNFKLVK
CTVQTEIREIITSILLSGRIGPNIRLAECYGLRLKHMKSDEIHWLHPQMTVGEVQDKYEC
LHVEAEWRYDLQIRYLPEDFMESLKEDRTTLLYFYQQLRNDYMQRYASKVSEGMALQLGC
LELRRFFKDMPHNALDKKSNFELLEKEVGLDLFFPKQMQENLKPKQFRKMIQQTFQQYAS
LREEECVMKFFNTLAGFANIDQETYRCELIQGWNITVDLVIGPKGIRQLTSQDAKPTCLA
EFKQIRSIRCLPLEEGQAVLQLGIEGAPQALSIKTSSLAEAENMADLIDGYCRLQGEHQG
SLIIHPRKDGEKRNSLPQIPMLNLEARRSHLSESCSIESDIYAEIPDETLRRPGGPQYGI
AREDVVLNRILGEGFFGEVYEGVYTNHKGEKINVAVKTCKKDCTLDNKEKFMSEAVIMKN
LDHPHIVKLIGIIEEEPTWIIMELYPYGELGHYLERNKNSLKVLTLVLYSLQICKAMAYL
ESINCVHRDIAVRNILVASPECVKLGDFGLSRYIEDEDYYKASVTRLPIKWMSPESINFR
RFTTASDVWMFAVCMWEILSFGKQPFFWLENKDVIGVLEKGDRLPKPDLCPPVLYTLMTR
CWDYDPSDRPRFTELVCSLSDVYQMEKDIAMEQERNARYRTPKILEPTAFQEPPPKPSRP
KYRPPPQTNLLAPKLQFQVPEGLCASSPTLTSPMEYPSPVNSLHTPPLHRHNVFKRHSMR
EEDFIQPSSREEAQQLWEAEKVKMRQILDKQQKQMVEDYQWLRQEEKSLDPMVYMNDKSP
LTPEKEVGYLEFTGPPQKPPRLGAQSIQPTANLDRTDDLVYLNVMELVRAVLELKNELCQ
LPPEGYVVVVKNVGLTLRKLIGSVDDLLPSLPSSSRTEIEGTQKLLNKDLAELINKMRLA
QQNAVTSLSEECKRQMLTASHTLAVDAKNLLDAVDQAKVLANLAHPPAE
Function
Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.
Tissue Specificity Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes.
KEGG Pathway
Calcium sig.ling pathway (hsa04020 )
Chemokine sig.ling pathway (hsa04062 )
Phospholipase D sig.ling pathway (hsa04072 )
.tural killer cell mediated cytotoxicity (hsa04650 )
Leukocyte transendothelial migration (hsa04670 )
GnRH sig.ling pathway (hsa04912 )
Yersinia infection (hsa05135 )
Hepatitis B (hsa05161 )
Human cytomegalovirus infection (hsa05163 )
Human immunodeficiency virus 1 infection (hsa05170 )
Reactome Pathway
VEGFA-VEGFR2 Pathway (R-HSA-4420097 )
RHOU GTPase cycle (R-HSA-9013420 )
Interleukin-2 signaling (R-HSA-9020558 )
Signal regulatory protein family interactions (R-HSA-391160 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
15 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [1]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [2]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [3]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide affects the expression of Protein-tyrosine kinase 2-beta (PTK2B). [5]
Dexamethasone DMMWZET Approved Dexamethasone increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [6]
Niclosamide DMJAGXQ Approved Niclosamide increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [7]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [10]
Tamibarotene DM3G74J Phase 3 Tamibarotene increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [1]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [12]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [13]
PMID25656651-Compound-5 DMAI95U Patented PMID25656651-Compound-5 decreases the activity of Protein-tyrosine kinase 2-beta (PTK2B). [14]
Sulforaphane DMQY3L0 Investigative Sulforaphane decreases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [16]
QUERCITRIN DM1DH96 Investigative QUERCITRIN affects the expression of Protein-tyrosine kinase 2-beta (PTK2B). [17]
Manganese DMKT129 Investigative Manganese decreases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [18]
Paraoxon DMN4ZKC Investigative Paraoxon increases the expression of Protein-tyrosine kinase 2-beta (PTK2B). [19]
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⏷ Show the Full List of 15 Drug(s)
6 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of Protein-tyrosine kinase 2-beta (PTK2B). [4]
Ethanol DMDRQZU Approved Ethanol increases the phosphorylation of Protein-tyrosine kinase 2-beta (PTK2B). [8]
Colchicine DM2POTE Approved Colchicine increases the phosphorylation of Protein-tyrosine kinase 2-beta (PTK2B). [9]
Rigosertib DMOSTXF Phase 3 Rigosertib increases the phosphorylation of Protein-tyrosine kinase 2-beta (PTK2B). [11]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Protein-tyrosine kinase 2-beta (PTK2B). [15]
Uric acid DMA1MKT Investigative Uric acid increases the phosphorylation of Protein-tyrosine kinase 2-beta (PTK2B). [20]
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⏷ Show the Full List of 6 Drug(s)

References

1 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
2 Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
3 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
4 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
5 Time-series analysis in imatinib-resistant chronic myeloid leukemia K562-cells under different drug treatments. J Huazhong Univ Sci Technolog Med Sci. 2017 Aug;37(4):621-627. doi: 10.1007/s11596-017-1781-1. Epub 2017 Aug 8.
6 Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
7 Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
8 Positive signaling interactions between arsenic and ethanol for angiogenic gene induction in human microvascular endothelial cells. Toxicol Sci. 2008 Apr;102(2):319-27. doi: 10.1093/toxsci/kfn003. Epub 2008 Jan 8.
9 Discovery of a novel compound: insight into mechanisms for acrylamide-induced axonopathy and colchicine-induced apoptotic neuronal cell death. Brain Res. 2001 Aug 3;909(1-2):8-19. doi: 10.1016/s0006-8993(01)02608-7.
10 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
11 Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
12 Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
13 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
14 AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
15 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
16 Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
17 Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
18 Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
19 Genomic and phenotypic alterations of the neuronal-like cells derived from human embryonal carcinoma stem cells (NT2) caused by exposure to organophosphorus compounds paraoxon and mipafox. Int J Mol Sci. 2014 Jan 9;15(1):905-26. doi: 10.3390/ijms15010905.
20 Flavonoids interfere with NLRP3 inflammasome activation. Toxicol Appl Pharmacol. 2018 Sep 15;355:93-102. doi: 10.1016/j.taap.2018.06.022. Epub 2018 Jun 28.