Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKYZ4OP)

• DOT Name: SH2/SH3 adapter protein NCK1 (NCK1)
• Synonyms: Cytoplasmic protein NCK1; NCK adapter protein 1; Nck-1; SH2/SH3 adapter protein NCK-alpha
• Gene Name: NCK1
• UniProt ID: NCK1_HUMAN
• PDB ID: 2CI8; 2CI9; 2CUB; 2JS0; 2JS2; 2JW4; 5QU1; 5QU2; 5QU3; 5QU4; 5QU5; 5QU6; 5QU7; 5QU8; 5QUA
• Pfam ID: PF00017 ; PF00018
• Sequence:
  MAEEVVVVAKFDYVAQQEQELDIKKNERLWLLDDSKSWWRVRNSMNKTGFVPSNYVERKN
  SARKASIVKNLKDTLGIGKVKRKPSVPDSASPADDSFVDPGERLYDLNMPAYVKFNYMAE
  REDELSLIKGTKVIVMEKCSDGWWRGSYNGQVGWFPSNYVTEEGDSPLGDHVGSLSEKLA
  AVVNNLNTGQVLHVVQALYPFSSSNDEELNFEKGDVMDVIEKPENDPEWWKCRKINGMVG
  LVPKNYVTVMQNNPLTSGLEPSPPQCDYIRPSLTGKFAGNPWYYGKVTRHQAEMALNERG
  HEGDFLIRDSESSPNDFSVSLKAQGKNKHFKVQLKETVYCIGQRKFSTMEELVEHYKKAP
  IFTSEQGEKLYLVKHLS
• Function: Adapter protein which associates with tyrosine-phosphorylated growth factor receptors, such as KDR and PDGFRB, or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in the DNA damage response, not in the detection of the damage by ATM/ATR, but for efficient activation of downstream effectors, such as that of CHEK2. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling. Modulates the activation of EIF2AK2/PKR by dsRNA. May play a role in cell adhesion and migration through interaction with ephrin receptors.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Axon guidance (hsa04360)
  T cell receptor sig.ling pathway (hsa04660)
  Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway:
  Generation of second messenger molecules (R-HSA-202433)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Nephrin family interactions (R-HSA-373753)
  DCC mediated attractive signaling (R-HSA-418885)
  Activation of RAC1 (R-HSA-428540)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RHOU GTPase cycle (R-HSA-9013420)
  RHOV GTPase cycle (R-HSA-9013424)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Potential therapeutics for SARS (R-HSA-9679191)
  PKR-mediated signaling (R-HSA-9833482)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  Downstream signal transduction (R-HSA-186763)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[8]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[10]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[6]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[13]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of SH2/SH3 adapter protein NCK1 (NCK1).	[14]

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 increases the methylation of SH2/SH3 adapter protein NCK1 (NCK1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of SH2/SH3 adapter protein NCK1 (NCK1).	[12]

References

• [1] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] 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.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] 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.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [14] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.