Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK4103B)

• DOT Name: Ly-6/neurotoxin-like protein 1 (LYNX1)
• Synonyms: Endogenous prototoxin LYNX1; Testicular tissue protein Li 112
• Gene Name: LYNX1
• Related Disease:
  Alzheimer disease
  Breast adenocarcinoma
  Breast neoplasm
  Cognitive impairment
  Colon carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Psoriasis
  Squamous cell carcinoma
  Asthma
• UniProt ID: LYNX1_HUMAN
• PDB ID: 2L03
• Pfam ID: PF00087
• Sequence:
  MTPLLTLILVVLMGLPLAQALDCHVCAYNGDNCFNPMRCPAMVAYCMTTRTYYTPTRMKV
  SKSCVPRCFETVYDGYSKHASTTSCCQYDLCNGTGLATPATLALAPILLATLWGLL
• Function: Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs). The proposed role as modulator of nAChR activity seems to be dependent on the nAChR subtype and stoichiometry, and to involve an effect on nAChR trafficking and its cell surface expression, and on single channel properties of the nAChR inserted in the plasma membrane. Modulates functional properties of nicotinic acetylcholine receptors (nAChRs) to prevent excessive excitation, and hence neurodegeneration. Enhances desensitization by increasing both the rate and extent of desensitization of alpha-4:beta-2-containing nAChRs and slowing recovery from desensitization. Promotes large amplitude ACh-evoked currents through alpha-4:beta-2 nAChRs. Is involved in regulation of the nAChR pentameric assembly in the endoplasmic reticulum. Shifts stoichiometry from high sensitivity alpha-4(2):beta-2(3) to low sensitivity alpha-4(3):beta-2(2) nAChR. In vitro modulates alpha-3:beta-4-containing nAChRs. Reduces cell surface expression of (alpha-3:beta-4)(2):beta-4 and (alpha-3:beta-4)(2):alpha-5 nAChRs suggesting an interaction with nAChR alpha-3(-):(+)beta-4 subunit interfaces and an allosteric mode. Corresponding single channel effects characterized by decreased unitary conductance, altered burst proportions and enhanced desensitization/inactivation seem to depend on nAChR alpha:alpha subunit interfaces and are greater in (alpha-3:beta-2)(2):alpha-3 when compared to (alpha-3:beta-2)(2):alpha-5 nAChRs. Prevents plasticity in the primary visual cortex late in life.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Breast adenocarcinoma	DISMPHJ0	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Psoriasis	DIS59VMN	Strong	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[2]
Asthma	DISW9QNS	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ly-6/neurotoxin-like protein 1 (LYNX1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ly-6/neurotoxin-like protein 1 (LYNX1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ly-6/neurotoxin-like protein 1 (LYNX1).	[8]

References

• [1] Lynx1 and A1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes.Neurobiol Aging. 2016 Oct;46:13-21. doi: 10.1016/j.neurobiolaging.2016.06.009. Epub 2016 Jun 17.
• [2] Water-soluble variant of human Lynx1 induces cell cycle arrest and apoptosis in lung cancer cells via modulation of 7 nicotinic acetylcholine receptors.PLoS One. 2019 May 31;14(5):e0217339. doi: 10.1371/journal.pone.0217339. eCollection 2019.
• [3] LY-6K gene: a novel molecular marker for human breast cancer.Oncol Rep. 2006 Dec;16(6):1211-4.
• [4] Lynx1 Prevents Long-Term Potentiation Blockade and Reduction of Neuromodulator Expression Caused by A1-42 and JNK Activation.Acta Naturae. 2018 Jul-Sep;10(3):57-61.
• [5] SLURP-2, a novel member of the human Ly-6 superfamily that is up-regulated in psoriasis vulgaris.Genomics. 2003 Jan;81(1):26-33. doi: 10.1016/s0888-7543(02)00025-3.
• [6] Role of Lynx1 and related Ly6 proteins as modulators of cholinergic signaling in normal and neoplastic bronchial epithelium.Int Immunopharmacol. 2015 Nov;29(1):93-8. doi: 10.1016/j.intimp.2015.05.022. Epub 2015 May 26.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.