Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB9N93T)

• DOT Name: Proto-oncogene DBL (MCF2)
• Synonyms: Proto-oncogene MCF-2
• Gene Name: MCF2
• Related Disease:
  B-cell neoplasm
  Familial isolated hypoparathyroidism due to agenesis of parathyroid gland
  Bilateral perisylvian polymicrogyria
  Germ cell tumor
  Ewing sarcoma
  Hepatocellular carcinoma
  Neoplasm
  Primitive neuroectodermal tumor
  Advanced cancer
  Malaria
• UniProt ID: MCF2_HUMAN
• Pfam ID: PF13716 ; PF00169 ; PF00621
• Sequence:
  MAEANPRRGKMRFRRNAASFPGNLHLVLVLRPTSFLQRTFTDIGFWFSQEDFMLKLPVVM
  LSSVSDLLTYIDDKQLTPELGGTLQYCHSEWIIFRNAIENFALTVKEMAQMLQSFGTELA
  ETELPDDIPSIEEILAIRAERYHLLKNDITAVTKEGKILLTNLEVPDTEGAVSSRLECHR
  QISGDWQTINKLLTQVHDMETAFDGFWEKHQLKMEQYLQLWKFEQDFQQLVTEVEFLLNQ
  QAELADVTGTIAQVKQKIKKLENLDENSQELLSKAQFVILHGHKLAANHHYALDLICQRC
  NELRYLSDILVNEIKAKRIQLSRTFKMHKLLQQARQCCDEGECLLANQEIDKFQSKEDAQ
  KALQDIENFLEMALPFINYEPETLQYEFDVILSPELKVQMKTIQLKLENIRSIFENQQAG
  FRNLADKHVRPIQFVVPTPENLVTSGTPFFSSKQGKKTWRQNQSNLKIEVVPDCQEKRSS
  GPSSSLDNGNSLDVLKNHVLNELIQTERVYVRELYTVLLGYRAEMDNPEMFDLMPPLLRN
  KKDILFGNMAEIYEFHNDIFLSSLENCAHAPERVGPCFLERKDDFQMYAKYCQNKPRSET
  IWRKYSECAFFQECQRKLKHRLRLDSYLLKPVQRITKYQLLLKELLKYSKDCEGSALLKK
  ALDAMLDLLKSVNDSMHQIAINGYIGNLNELGKMIMQGGFSVWIGHKKGATKMKDLARFK
  PMQRHLFLYEKAIVFCKRRVESGEGSDRYPSYSFKHCWKMDEVGITEYVKGDNRKFEIWY
  GEKEEVYIVQASNVDVKMTWLKEIRNILLKQQELLTVKKRKQQDQLTERDKFQISLQQND
  EKQQGAFISTEETELEHTSTVVEVCEAIASVQAEANTVWTEASQSAEISEEPAEWSSNYF
  YPTYDENEEENRPLMRPVSEMALLY
• Function: Guanine nucleotide exchange factor (GEF) that modulates the Rho family of GTPases. Promotes the conversion of some member of the Rho family GTPase from the GDP-bound to the GTP-bound form. Isoform 1 exhibits no activity toward RHOA, RAC1 or CDC42. Isoform 2 exhibits decreased GEF activity toward CDC42. Isoform 3 exhibits a weak but significant activity toward RAC1 and CDC42. Isoform 4 exhibits significant activity toward RHOA and CDC42. The truncated DBL oncogene is active toward RHOA, RAC1 and CDC42.
• Tissue Specificity: Isoform 1 is expressed only in brain. Isoform 3 is expressed in heart, kidney, spleen, liver and testis. Isoform 4 is expressed in brain, heart, kidney, testis, placenta, stomach and peripheral blood. The protein is detectable in brain, heart, kidney, intestine, muscle, lung and testis.
• Reactome Pathway:
  NRAGE signals death through JNK (R-HSA-193648)
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  RAC3 GTPase cycle (R-HSA-9013423)
  Axonal growth inhibition (RHOA activation) (R-HSA-193634)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Familial isolated hypoparathyroidism due to agenesis of parathyroid gland	DISPDS1V	Definitive	Biomarker	[2]
Bilateral perisylvian polymicrogyria	DISIF9XK	Strong	Genetic Variation	[3]
Germ cell tumor	DIS62070	Strong	Biomarker	[4]
Ewing sarcoma	DISQYLV3	moderate	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[5]
Primitive neuroectodermal tumor	DISFHXHA	moderate	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Malaria	DISQ9Y50	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proto-oncogene DBL (MCF2).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Proto-oncogene DBL (MCF2).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Proto-oncogene DBL (MCF2).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Proto-oncogene DBL (MCF2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Proto-oncogene DBL (MCF2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proto-oncogene DBL (MCF2).	[15]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Proto-oncogene DBL (MCF2).	[14]

References

• [1] The predicted DBL oncogene product defines a distinct class of transforming proteins.Proc Natl Acad Sci U S A. 1988 Apr;85(7):2061-5. doi: 10.1073/pnas.85.7.2061.
• [2] X-linked hypoparathyroidism region on Xq27 is evolutionarily conserved with regions on 3q26 and 13q34 and contains a novel P-type ATPase.Genomics. 2004 Dec;84(6):1060-70. doi: 10.1016/j.ygeno.2004.08.003.
• [3] MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination.Ann Clin Transl Neurol. 2020 Jan;7(1):121-125. doi: 10.1002/acn3.50949. Epub 2019 Dec 17.
• [4] Mutational analysis of proto-oncogene Dbl on Xq27 in testicular germ cell tumors reveals a rare SNP in a patient with bilateral undescended testis.World J Urol. 2009 Dec;27(6):811-5. doi: 10.1007/s00345-009-0408-y.
• [5] Expression of the dbl proto-oncogene in Ewing's sarcomas.Oncogene. 1989 Jul;4(7):897-900.
• [6] Multi-color RGB marking enables clonality assessment of liver tumors in a murine xenograft model.Oncotarget. 2017 Dec 14;8(70):115582-115595. doi: 10.18632/oncotarget.23312. eCollection 2017 Dec 29.
• [7] Purification, characterization and biological significance of mannose binding lectin from Dioscorea bulbifera bulbils.Int J Biol Macromol. 2017 Sep;102:1146-1155. doi: 10.1016/j.ijbiomac.2017.04.085. Epub 2017 May 1.
• [8] Serologic responses to the PfEMP1 DBL-CIDR head structure may be a better indicator of malaria exposure than those to the DBL- tag.Malar J. 2019 Aug 13;18(1):273. doi: 10.1186/s12936-019-2905-9.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] 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.