Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8G13EG)

• DOT Name: Neuronal membrane glycoprotein M6-a (GPM6A)
• Synonyms: M6a
• Gene Name: GPM6A
• Related Disease:
  Hepatocellular carcinoma
  Alzheimer disease
  Depression
  Major depressive disorder
  Mental disorder
  Mood disorder
  Panic disorder
  Advanced cancer
  Schizophrenia
  Small lymphocytic lymphoma
  Small-cell lung cancer
  Neuroblastoma
  Non-insulin dependent diabetes
• UniProt ID: GPM6A_HUMAN
• Pfam ID: PF01275
• Sequence:
  MEENMEEGQTQKGCFECCIKCLGGIPYASLIATILLYAGVALFCGCGHEALSGTVNILQT
  YFEMARTAGDTLDVFTMIDIFKYVIYGIAAAFFVYGILLMVEGFFTTGAIKDLYGDFKIT
  TCGRCVSAWFIMLTYLFMLAWLGVTAFTSLPVYMYFNLWTICRNTTLVEGANLCLDLRQF
  GIVTIGEEKKICTVSENFLRMCESTELNMTFHLFIVALAGAGAAVIAMVHYLMVLSANWA
  YVKDACRMQKYEDIKSKEEQELHDIHSTRSKERLNAYT
• Function: Involved in neuronal differentiation, including differentiation and migration of neuronal stem cells. Plays a role in neuronal plasticity and is involved in neurite and filopodia outgrowth, filopodia motility and probably synapse formation. GPM6A-induced filopodia formation involves mitogen-activated protein kinase (MAPK) and Src signaling pathways. May be involved in neuronal NGF-dependent Ca(2+) influx. May be involved in regulation of endocytosis and intracellular trafficking of G-protein-coupled receptors (GPCRs); enhances internalization and recycling of mu-type opioid receptor.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Depression	DIS3XJ69	Strong	Genetic Variation	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[2]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[4]
Panic disorder	DISD3VNY	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[7]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[8]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[9]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[11]

10 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 Neuronal membrane glycoprotein M6-a (GPM6A).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[16]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[18]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuronal membrane glycoprotein M6-a (GPM6A).	[22]

1 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 Neuronal membrane glycoprotein M6-a (GPM6A).	[19]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] The Membrane Glycoprotein M6a Endocytic/Recycling Pathway Involves Clathrin-Mediated Endocytosis and Affects Neuronal Synapses.Front Mol Neurosci. 2017 Sep 20;10:296. doi: 10.3389/fnmol.2017.00296. eCollection 2017.
• [3] Do mood symptoms subdivide the schizophrenia phenotype? Association of the GMP6A gene with a depression subgroup.Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):707-11. doi: 10.1002/ajmg.b.30667.
• [4] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [5] A single gene defect causing claustrophobia.Transl Psychiatry. 2013 Apr 30;3(4):e254. doi: 10.1038/tp.2013.28.
• [6] Identification of GPM6A and GPM6B as potential new human lymphoid leukemia-associated oncogenes.Cell Oncol (Dordr). 2014 Jun;37(3):179-91. doi: 10.1007/s13402-014-0171-y. Epub 2014 Jun 12.
• [7] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [8] A seven-gene expression panel distinguishing clonal expansions of pre-leukemic and chronic lymphocytic leukemia B cells from normal B lymphocytes.Immunol Res. 2015 Dec;63(1-3):90-100. doi: 10.1007/s12026-015-8688-3.
• [9] miR-22 enhances the radiosensitivity of small-cell lung cancer by targeting the WRNIP1.J Cell Biochem. 2019 Oct;120(10):17650-17661. doi: 10.1002/jcb.29032. Epub 2019 Jun 12.
• [10] Alanine Scanning Mutagenesis of the C-Terminal Cytosolic End of Gpm6a Identifies Key Residues Essential for the Formation of Filopodia.Front Mol Neurosci. 2018 Sep 4;11:314. doi: 10.3389/fnmol.2018.00314. eCollection 2018.
• [11] Identification of a genetic locus on chromosome 4q34-35 for type 2 diabetes with overweight.Exp Mol Med. 2013 Feb 8;45(2):e7. doi: 10.1038/emm.2013.5.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [18] 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.
• [19] 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.
• [20] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [21] Proteomics and disease network associations evaluation of environmentally relevant Bisphenol A concentrations in a human 3D neural stem cell model. Front Cell Dev Biol. 2023 Aug 16;11:1236243. doi: 10.3389/fcell.2023.1236243. eCollection 2023.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.