Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB3015O)

• DOT Name: Protein lin-7 homolog C (LIN7C)
• Synonyms: Lin-7C; Mammalian lin-seven protein 3; MALS-3; Vertebrate lin-7 homolog 3; Veli-3
• Gene Name: LIN7C
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Drug dependence
  Squamous cell carcinoma
  Pancreatic cancer
  Non-insulin dependent diabetes
• UniProt ID: LIN7C_HUMAN
• PDB ID: 3LRA
• Pfam ID: PF02828 ; PF00595
• Sequence:
  MAALGEPVRLERDICRAIELLEKLQRSGEVPPQKLQALQRVLQSEFCNAVREVYEHVYET
  VDISSSPEVRANATAKATVAAFAASEGHSHPRVVELPKTEEGLGFNIMGGKEQNSPIYIS
  RIIPGGIADRHGGLKRGDQLLSVNGVSVEGEHHEKAVELLKAAQGKVKLVVRYTPKVLEE
  MESRFEKMRSAKRRQQT
• Function: Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells. Forms membrane-associated multiprotein complexes that may regulate delivery and recycling of proteins to the correct membrane domains. The tripartite complex composed of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1 associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules. This complex may have the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Ensures the proper localization of GRIN2B (subunit 2B of the NMDA receptor) to neuronal postsynaptic density and may function in localizing synaptic vesicles at synapses where it is recruited by beta-catenin and cadherin. Required to localize Kir2 channels, GABA transporter (SLC6A12) and EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 to the basolateral membrane of epithelial cells.
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[1]
Drug dependence	DIS9IXRC	Strong	Genetic Variation	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Protein lin-7 homolog C (LIN7C) affects the response to substance of Topotecan.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein lin-7 homolog C (LIN7C).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein lin-7 homolog C (LIN7C).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein lin-7 homolog C (LIN7C).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein lin-7 homolog C (LIN7C).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein lin-7 homolog C (LIN7C).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein lin-7 homolog C (LIN7C).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein lin-7 homolog C (LIN7C).	[12]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Protein lin-7 homolog C (LIN7C).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein lin-7 homolog C (LIN7C).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein lin-7 homolog C (LIN7C).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein lin-7 homolog C (LIN7C).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Protein lin-7 homolog C (LIN7C).	[17]

References

• [1] Apico-basal polarity in polycystic kidney disease epithelia.Biochim Biophys Acta. 2011 Oct;1812(10):1239-48. doi: 10.1016/j.bbadis.2011.05.008. Epub 2011 Jun 1.
• [2] The relationship between polymorphisms of BDNFOS and BDNF genes and heroin addiction in the Han Chinese population.J Gene Med. 2016 Oct;18(10):288-293. doi: 10.1002/jgm.2927.
• [3] Lin-7C/VELI3/MALS-3: an essential component in metastasis of human squamous cell carcinoma.Cancer Res. 2007 Oct 15;67(20):9643-8. doi: 10.1158/0008-5472.CAN-07-1911.
• [4] Genetic polymorphisms associated with pancreatic cancer survival: a genome-wide association study.Int J Cancer. 2017 Aug 15;141(4):678-686. doi: 10.1002/ijc.30762. Epub 2017 May 15.
• [5] Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese.J Clin Endocrinol Metab. 2010 May;95(5):2418-25. doi: 10.1210/jc.2009-2077. Epub 2010 Mar 9.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] 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.
• [8] 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.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] 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.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [17] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.