Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUYPF55)

• DOT Name: Cytoplasmic protein NCK2 (NCK2)
• Synonyms: Growth factor receptor-bound protein 4; NCK adaptor protein 2; Nck-2; SH2/SH3 adaptor protein NCK-beta
• Gene Name: NCK2
• Related Disease:
  Cognitive impairment
  Epithelial ovarian cancer
  Fatty liver disease
  Melanoma
  Neoplasm
  Nephrotic syndrome
  Noonan syndrome
  Ovarian cancer
  Ovarian neoplasm
  Parkinson disease
  Retinopathy
  Glaucoma/ocular hypertension
• UniProt ID: NCK2_HUMAN
• PDB ID: 1U5S; 1WX6; 1Z3K; 2B86; 2CIA; 2FRW; 2FRY; 2JXB; 4E6R
• Pfam ID: PF00017 ; PF00018 ; PF14604
• Sequence:
  MTEEVIVIAKWDYTAQQDQELDIKKNERLWLLDDSKTWWRVRNAANRTGYVPSNYVERKN
  SLKKGSLVKNLKDTLGLGKTRRKTSARDASPTPSTDAEYPANGSGADRIYDLNIPAFVKF
  AYVAEREDELSLVKGSRVTVMEKCSDGWWRGSYNGQIGWFPSNYVLEEVDEAAAESPSFL
  SLRKGASLSNGQGSRVLHVVQTLYPFSSVTEEELNFEKGETMEVIEKPENDPEWWKCKNA
  RGQVGLVPKNYVVVLSDGPALHPAHAPQISYTGPSSSGRFAGREWYYGNVTRHQAECALN
  ERGVEGDFLIRDSESSPSDFSVSLKASGKNKHFKVQLVDNVYCIGQRRFHTMDELVEHYK
  KAPIFTSEHGEKLYLVRALQ
• Function: Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Axon guidance (hsa04360)
  T cell receptor sig.ling pathway (hsa04660)
  Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway:
  Nephrin family interactions (R-HSA-373753)
  Ephrin signaling (R-HSA-3928664)
  Activation of RAC1 (R-HSA-428540)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Regulation of cortical dendrite branching (R-HSA-8985801)
  RHOU GTPase cycle (R-HSA-9013420)
  RHOV GTPase cycle (R-HSA-9013424)
  Downstream signal transduction (R-HSA-186763)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[5]
Noonan syndrome	DIS7Q7DN	Strong	Biomarker	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[6]
Retinopathy	DISB4B0F	moderate	Biomarker	[7]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[8]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cytoplasmic protein NCK2 (NCK2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytoplasmic protein NCK2 (NCK2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[15]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[16]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytoplasmic protein NCK2 (NCK2).	[17]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytoplasmic protein NCK2 (NCK2).	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytoplasmic protein NCK2 (NCK2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Cytoplasmic protein NCK2 (NCK2).	[20]

References

• [1] Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function.Cell Rep. 2018 Aug 7;24(6):1523-1535. doi: 10.1016/j.celrep.2018.07.006.
• [2] Non-catalytic region of tyrosine kinase adaptor protein 2 (NCK2) pathways as factor promoting aggressiveness in ovarian cancer.Int J Biol Markers. 2018 Jan;33(1):124-131. doi: 10.5301/ijbm.5000264.
• [3] Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis.Diabetes. 2016 Sep;65(9):2652-66. doi: 10.2337/db15-1559. Epub 2016 Jun 20.
• [4] Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo.BMC Cancer. 2011 Oct 12;11:443. doi: 10.1186/1471-2407-11-443.
• [5] Nck proteins maintain the adult glomerular filtration barrier.J Am Soc Nephrol. 2009 Jul;20(7):1533-43. doi: 10.1681/ASN.2009010056. Epub 2009 May 14.
• [6] Identification of crucial genes associated with Parkinson's disease using microarray data.Mol Med Rep. 2018 Mar;17(3):3775-3782. doi: 10.3892/mmr.2017.8305. Epub 2017 Dec 18.
• [7] NCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy.Nat Commun. 2018 Aug 27;9(1):3463. doi: 10.1038/s41467-018-05926-7.
• [8] Microsatellite analysis of the GLC1B locus on chromosome 2 points to NCK2 as a new candidate gene for normal tension glaucoma.Br J Ophthalmol. 2008 Sep;92(9):1293-6. doi: 10.1136/bjo.2008.139980.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] 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.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [20] 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.