Details of Drug Off-Target (DOT)

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

• DOT Name: MAP kinase-activating death domain protein (MADD)
• Synonyms: Differentially expressed in normal and neoplastic cells; Insulinoma glucagonoma clone 20; Rab3 GDP/GTP exchange factor; RabGEF; Rab3 GDP/GTP exchange protein; Rab3GEP
• Gene Name: MADD
• Related Disease:
  Neuroblastoma
  Alzheimer disease
  Anxiety
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Frontometaphyseal dysplasia
  Gastric cancer
  Insomnia
  Multiple acyl-CoA dehydrogenase deficiency
  Neoplasm
  Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
  Open-angle glaucoma
  Stomach cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland follicular carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  Type-1/2 diabetes
  Syndromic intellectual disability
  Intellectual disability
  Metastatic malignant neoplasm
  Advanced cancer
  Coronary atherosclerosis
  Coronary heart disease
  Glycogen storage disease III
  Glycogen storage disease V
  Metabolic myopathy
  Systemic primary carnitine deficiency disease
• UniProt ID: MADD_HUMAN
• Pfam ID: PF02141 ; PF03456
• Sequence:
  MVQKKKFCPRLLDYLVIVGARHPSSDSVAQTPELLRRYPLEDHTEFPLPPDVVFFCQPEG
  CLSVRQRRMSLRDDTSFVFTLTDKDTGVTRYGICVNFYRSFQKRISKEKGEGGAGSRGKE
  GTHATCASEEGGTESSESGSSLQPLSADSTPDVNQSPRGKRRAKAGSRSRNSTLTSLCVL
  SHYPFFSTFRECLYTLKRLVDCCSERLLGKKLGIPRGVQRDTMWRIFTGSLLVEEKSSAL
  LHDLREIEAWIYRLLRSPVPVSGQKRVDIEVLPQELQPALTFALPDPSRFTLVDFPLHLP
  LELLGVDACLQVLTCILLEHKVVLQSRDYNALSMSVMAFVAMIYPLEYMFPVIPLLPTCM
  ASAEQLLLAPTPYIIGVPASFFLYKLDFKMPDDVWLVDLDSNRVIAPTNAEVLPILPEPE
  SLELKKHLKQALASMSLNTQPILNLEKFHEGQEIPLLLGRPSNDLQSTPSTEFNPLIYGN
  DVDSVDVATRVAMVRFFNSANVLQGFQMHTRTLRLFPRPVVAFQAGSFLASRPRQTPFAE
  KLARTQAVEYFGEWILNPTNYAFQRIHNNMFDPALIGDKPKWYAHQLQPIHYRVYDSNSQ
  LAEALSVPPERDSDSEPTDDSGSDSMDYDDSSSSYSSLGDFVSEMMKCDINGDTPNVDPL
  THAALGDASEVEIDELQNQKEAEEPGPDSENSQENPPLRSSSSTTASSSPSTVIHGANSE
  PADSTEMDDKAAVGVSKPLPSVPPSIGKSNVDRRQAEIGEGSVRRRIYDNPYFEPQYGFP
  PEEDEDEQGESYTPRFSQHVSGNRAQKLLRPNSLRLASDSDAESDSRASSPNSTVSNTST
  EGFGGIMSFASSLYRNHSTSFSLSNLTLPTKGAREKATPFPSLKVFGLNTLMEIVTEAGP
  GSGEGNRRALVDQKSSVIKHSPTVKREPPSPQGRSSNSSENQQFLKEVVHSVLDGQGVGW
  LNMKKVRRLLESEQLRVFVLSKLNRMVQSEDDARQDIIPDVEISRKVYKGMLDLLKCTVL
  SLEQSYAHAGLGGMASIFGLLEIAQTHYYSKEPDKRKRSPTESVNTPVGKDPGLAGRGDP
  KAMAQLRVPQLGPRAPSATGKGPKELDTRSLKEENFIASIELWNKHQEVKKQKALEKQRP
  EVIKPVFDLGETEEKKSQISADSGVSLTSSSQRTDQDSVIGVSPAVMIRSSSQDSEVSTV
  VSNSSGETLGADSDLSSNAGDGPGGEGSVHLASSRGTLSDSEIETNSATSTIFGKAHSLK
  PSIKEKLAGSPIRTSEDVSQRVYLYEGLLGRDKGSMWDQLEDAAMETFSISKERSTLWDQ
  MQFWEDAFLDAVMLEREGMGMDQGPQEMIDRYLSLGEHDRKRLEDDEDRLLATLLHNLIS
  YMLLMKVNKNDIRKKVRRLMGKSHIGLVYSQQINEVLDQLANLNGRDLSIWSSGSRHMKK
  QTFVVHAGTDTNGDIFFMEVCDDCVVLRSNIGTVYERWWYEKLINMTYCPKTKVLCLWRR
  NGSETQLNKFYTKKCRELYYCVKDSMERAAARQQSIKPGPELGGEFPVQDLKTGEGGLLQ
  VTLEGINLKFMHNQVFIELNHIKKCNTVRGVFVLEEFVPEIKEVVSHKYKTPMAHEICYS
  VLCLFSYVAAVHSSEEDLRTPPRPVSS
• Function: Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family. Converts GDP-bound inactive form of RAB27A and RAB27B to the GTP-bound active forms. Converts GDP-bound inactive form of RAB3A, RAB3C and RAB3D to the GTP-bound active forms, GTPases involved in synaptic vesicle exocytosis and vesicle secretion. Plays a role in synaptic vesicle formation and in vesicle trafficking at the neuromuscular junction. Involved in up-regulating a post-docking step of synaptic exocytosis in central synapses. Probably by binding to the motor proteins KIF1B and KIF1A, mediates motor-dependent transport of GTP-RAB3A-positive vesicles to the presynaptic nerve terminals. Plays a role in TNFA-mediated activation of the MAPK pathway, including ERK1/2. May link TNFRSF1A with MAP kinase activation. May be involved in the regulation of TNFA-induced apoptosis.
• Tissue Specificity: Expressed in testis, ovary, brain and heart . Expressed in spleen, thymus, prostate, testis, ovary, small instestine and colon . Expressed in liver .; [Isoform 1]: Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.; [Isoform 2]: Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.; [Isoform 3]: Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.; [Isoform 4]: Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.; [Isoform 5]: Expressed in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.; [Isoform 6]: Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.; [Isoform 7]: Not detected in the brain, breast, kidney, lung, ovary, pancreas, testis, uterus, stomach and thyroid.
• Reactome Pathway:
  (Name not found)
  Regulation of TNFR1 signaling (R-HSA-5357905)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[5]
Frontometaphyseal dysplasia	DISXFPAW	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[7]
Insomnia	DIS0AFR7	Strong	Biomarker	[8]
Multiple acyl-CoA dehydrogenase deficiency	DISEFBN7	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia	DISWP6DO	Strong	Autosomal recessive	[11]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[12]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[7]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[13]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[13]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Biomarker	[13]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[10]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[13]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[14]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[15]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[16]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[17]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[18]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[18]
Glycogen storage disease III	DISTXQ1P	Limited	Genetic Variation	[19]
Glycogen storage disease V	DISJNC0O	Limited	Genetic Variation	[19]
Metabolic myopathy	DISSE3BW	Limited	Biomarker	[19]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[19]

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 MAP kinase-activating death domain protein (MADD).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MAP kinase-activating death domain protein (MADD).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of MAP kinase-activating death domain protein (MADD).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MAP kinase-activating death domain protein (MADD).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MAP kinase-activating death domain protein (MADD).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of MAP kinase-activating death domain protein (MADD).	[23]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of MAP kinase-activating death domain protein (MADD).	[24]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of MAP kinase-activating death domain protein (MADD).	[25]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of MAP kinase-activating death domain protein (MADD).	[26]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of MAP kinase-activating death domain protein (MADD).	[27]
Menthol	DMG2KW7	Approved	Menthol increases the expression of MAP kinase-activating death domain protein (MADD).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MAP kinase-activating death domain protein (MADD).	[29]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of MAP kinase-activating death domain protein (MADD).	[30]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of MAP kinase-activating death domain protein (MADD).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of MAP kinase-activating death domain protein (MADD).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MAP kinase-activating death domain protein (MADD).	[32]

References

• [1] Regulation of apoptosis and caspase-8 expression in neuroblastoma cells by isoforms of the IG20 gene.Cancer Res. 2008 Sep 15;68(18):7352-61. doi: 10.1158/0008-5472.CAN-07-6311.
• [2] Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis.Hum Genet. 2019 Mar;138(3):271-285. doi: 10.1007/s00439-019-01988-9. Epub 2019 Feb 25.
• [3] 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.
• [4] TRAIL suppresses human breast cancer cell migration via MADD/CXCR7.Asian Pac J Cancer Prev. 2015;16(7):2751-6. doi: 10.7314/apjcp.2015.16.7.2751.
• [5] Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus.Oncol Rep. 2014 Feb;31(2):693-700. doi: 10.3892/or.2013.2901. Epub 2013 Dec 5.
• [6] Structural and thermodynamic basis of a frontometaphyseal dysplasia mutation in filamin A.J Biol Chem. 2017 May 19;292(20):8390-8400. doi: 10.1074/jbc.M117.776740. Epub 2017 Mar 27.
• [7] Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer.Gastric Cancer. 2015 Apr;18(2):288-96. doi: 10.1007/s10120-014-0372-0. Epub 2014 Apr 3.
• [8] Integrative analysis of genome-wide association study and brain region related enhancer maps identifies biological pathways for insomnia.Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:180-185. doi: 10.1016/j.pnpbp.2018.05.026. Epub 2018 Jun 6.
• [9] A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency.J Neurol Sci. 2018 Jan 15;384:121-125. doi: 10.1016/j.jns.2017.11.012. Epub 2017 Nov 15.
• [10] Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer.Cell Death Dis. 2019 Feb 13;10(2):145. doi: 10.1038/s41419-019-1351-5.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci.Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.
• [13] Knockdown of IG20 gene expression renders thyroid cancer cells susceptible to apoptosis.J Clin Endocrinol Metab. 2009 Apr;94(4):1467-71. doi: 10.1210/jc.2008-2378. Epub 2009 Feb 3.
• [14] Exome sequencing and genetic testing for MODY.PLoS One. 2012;7(5):e38050. doi: 10.1371/journal.pone.0038050. Epub 2012 May 25.
• [15] Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder. Brain. 2020 Aug 1;143(8):2437-2453. doi: 10.1093/brain/awaa204.
• [16] Expanding the genetic heterogeneity of intellectual disability.Hum Genet. 2017 Nov;136(11-12):1419-1429. doi: 10.1007/s00439-017-1843-2. Epub 2017 Sep 22.
• [17] MADD silencing enhances anti-tumor activity of TRAIL in anaplastic thyroid cancer.Endocr Relat Cancer. 2019 Jun 1;26(6):551-563. doi: 10.1530/ERC-18-0517.
• [18] MADD-FOLH1 Polymorphisms and Their Haplotypes with Serum Lipid Levels and the Risk of Coronary Heart Disease and Ischemic Stroke in a Chinese Han Population.Nutrients. 2016 Apr 8;8(4):208. doi: 10.3390/nu8040208.
• [19] Spectrum of metabolic myopathies.Biochim Biophys Acta. 2015 Apr;1852(4):615-21. doi: 10.1016/j.bbadis.2014.06.031. Epub 2014 Jul 2.
• [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] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [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] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [24] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [25] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [26] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [27] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [28] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [31] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [32] 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.
• [33] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [34] 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.