Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUWA6NW)

• DOT Name: Transmembrane protein 106B (TMEM106B)
• Gene Name: TMEM106B
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Brain disease
  Cognitive impairment
  Congenital diarrhea 5 with tufting enteropathy
  Depression
  Frontotemporal dementia
  Huntington disease
  Leukodystrophy, hypomyelinating, 16
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Mood disorder
  Motor neurone disease
  Neuronal ceroid lipofuscinosis
  Non-small-cell lung cancer
  Parkinson disease
  Pick disease
  Progressive supranuclear palsy
  Behavioral variant of frontotemporal dementia
  Colorectal carcinoma
  Coronary heart disease
  Leukodystrophy
  Progressive non-fluent aphasia
  Semantic dementia
• UniProt ID: T106B_HUMAN
• PDB ID: 7QVC; 7QVF; 7QWG; 7QWL; 7QWM; 7SAQ; 7SAR; 7SAS; 7TMC; 7U10; 7U11; 7U12; 7U13; 7U14; 7U15; 7U16; 7U17; 7U18; 7X83; 7X84; 8B7D; 8F9K
• Pfam ID: PF07092 ; PF21002
• Sequence:
  MGKSLSHLPLHSSKEDAYDGVTSENMRNGLVNSEVHNEDGRNGDVSQFPYVEFTGRDSVT
  CPTCQGTGRIPRGQENQLVALIPYSDQRLRPRRTKLYVMASVFVCLLLSGLAVFFLFPRS
  IDVKYIGVKSAYVSYDVQKRTIYLNITNTLNITNNNYYSVEVENITAQVQFSKTVIGKAR
  LNNITIIGPLDMKQIDYTVPTVIAEEMSYMYDFCTLISIKVHNIVLMMQVTVTTTYFGHS
  EQISQERYQYVDCGRNTTYQLGQSEYLNVLQPQQ
• Function: In neurons, involved in the transport of late endosomes/lysosomes. May be involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking. May act as a molecular brake for retrograde transport of late endosomes/lysosomes, possibly via its interaction with MAP6. In motoneurons, may mediate the axonal transport of lysosomes and axonal sorting at the initial segment. It remains unclear whether TMEM106B affects the transport of moving lysosomes in the anterograde or retrograde direction in neurites and whether it is important in the sorting of lysosomes in axons or in dendrites. In neurons, may also play a role in the regulation of lysosomal size and responsiveness to stress. Required for proper lysosomal acidification; (Microbial infection) Plays a role in human coronavirus SARS-CoV-2 infection, but not in common cold coronaviruses HCoV-229E and HCoV-OC43 infections. Involved in ACE2-independent SARS-CoV-2 cell entry. Required for post-endocytic stage of virus entry, facilitates spike-mediated membrane fusion. Virus attachment and endocytosis can also be mediated by other cell surface receptors.
• Tissue Specificity: Expressed in the brain, including in the frontal cortex (at protein level) . Expressed in lung epithelial cells .

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[3]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[4]
Cognitive impairment	DISH2ERD	Strong	Genetic Variation	[4]
Congenital diarrhea 5 with tufting enteropathy	DISPAMX4	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Leukodystrophy, hypomyelinating, 16	DISN15TG	Strong	Autosomal dominant	[9]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[11]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[12]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[13]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Strong	Altered Expression	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[10]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[7]
Pick disease	DISP6X50	Strong	Biomarker	[7]
Progressive supranuclear palsy	DISO5KRQ	Strong	Genetic Variation	[15]
Behavioral variant of frontotemporal dementia	DISQHX2V	moderate	SusceptibilityMutation	[16]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[17]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[18]
Leukodystrophy	DISVY1TT	moderate	Genetic Variation	[19]
Progressive non-fluent aphasia	DIS9HZET	moderate	SusceptibilityMutation	[16]
Semantic dementia	DISA7775	moderate	SusceptibilityMutation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transmembrane protein 106B (TMEM106B).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transmembrane protein 106B (TMEM106B).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transmembrane protein 106B (TMEM106B).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 106B (TMEM106B).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 106B (TMEM106B).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Transmembrane protein 106B (TMEM106B).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transmembrane protein 106B (TMEM106B).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transmembrane protein 106B (TMEM106B).	[25]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transmembrane protein 106B (TMEM106B).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transmembrane protein 106B (TMEM106B).	[26]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Transmembrane protein 106B (TMEM106B).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transmembrane protein 106B (TMEM106B).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Transmembrane protein 106B (TMEM106B).	[31]

References

• [1] TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins.Nat Commun. 2018 Jul 16;9(1):2731. doi: 10.1038/s41467-018-05013-x.
• [2] CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.Exp Gerontol. 2017 Apr;90:83-89. doi: 10.1016/j.exger.2017.01.025. Epub 2017 Feb 9.
• [3] Defining the association of TMEM106B variants among frontotemporal lobar degeneration patients with GRN mutations andC9orf72 repeat expansions.Neurobiol Aging. 2014 Nov;35(11):2658.e1-2658.e5. doi: 10.1016/j.neurobiolaging.2014.06.023. Epub 2014 Jun 28.
• [4] Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes.Cell Syst. 2017 Apr 26;4(4):404-415.e5. doi: 10.1016/j.cels.2017.02.009. Epub 2017 Mar 18.
• [5] Variation in TMEM106B in chronic traumatic encephalopathy.Acta Neuropathol Commun. 2018 Nov 4;6(1):115. doi: 10.1186/s40478-018-0619-9.
• [6] TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways.J Neurosci. 2012 Aug 15;32(33):11213-27. doi: 10.1523/JNEUROSCI.0521-12.2012.
• [7] TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia.Ann Neurol. 2019 Jun;85(6):801-811. doi: 10.1002/ana.25486.
• [8] Epigenetic dysregulation of hairy and enhancer of split 4 (HES4) is associated with striatal degeneration in postmortem Huntington brains.Hum Mol Genet. 2015 Mar 1;24(5):1441-56. doi: 10.1093/hmg/ddu561. Epub 2014 Dec 5.
• [9] The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J. 2014 Mar 3;33(5):450-67. doi: 10.1002/embj.201385857. Epub 2013 Dec 19.
• [10] Identification of a novel TMEM106B-ROS1 fusion variant in lung adenocarcinoma by comprehensive genomic profiling.Lung Cancer. 2015 Jun;88(3):352-4. doi: 10.1016/j.lungcan.2015.03.014. Epub 2015 Mar 21.
• [11] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [12] 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.
• [13] TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia.Acta Neuropathol. 2014 Mar;127(3):397-406. doi: 10.1007/s00401-013-1240-4. Epub 2014 Jan 3.
• [14] Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis.Acta Neuropathol. 2014;127(6):845-60. doi: 10.1007/s00401-014-1262-6. Epub 2014 Mar 12.
• [15] TMEM106B haplotypes have distinct gene expression patterns in aged brain.Mol Neurodegener. 2018 Jul 3;13(1):35. doi: 10.1186/s13024-018-0268-2.
• [16] What we know about TMEM106B in neurodegeneration.Acta Neuropathol. 2016 Nov;132(5):639-651. doi: 10.1007/s00401-016-1610-9. Epub 2016 Aug 20.
• [17] Long noncoding MAGI2-AS3 promotes colorectal cancer progression through regulating miR-3163/TMEM106B axis.J Cell Physiol. 2020 May;235(5):4824-4833. doi: 10.1002/jcp.29360. Epub 2019 Nov 10.
• [18] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [19] A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy.Brain. 2017 Dec 1;140(12):3105-3111. doi: 10.1093/brain/awx314.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [24] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [27] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.