Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBB8NO8)

• DOT Name: Myotubularin-related protein 13 (SBF2)
• Synonyms: Inactive phosphatidylinositol 3-phosphatase 13; SET-binding factor 2
• Gene Name: SBF2
• Related Disease:
  Charcot-Marie-Tooth disease type 1B
  Charcot-Marie-Tooth disease type 4B1
  Charcot-Marie-Tooth disease type 4B2
  Charcot marie tooth disease
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Demyelinating polyneuropathy
  Esophageal squamous cell carcinoma
  Griscelli syndrome
  Helicoid peripapillary chorioretinal degeneration
  Neuromuscular disease
  Pancreatic adenocarcinoma
  Pancreatic cancer
  Thrombocytopenia
  Moyamoya disease
  Hereditary glaucoma
  Acute myelogenous leukaemia
  Charcot-Marie-Tooth disease type 3
  Charcot-Marie-Tooth disease type 4
  Hereditary motor and sensory neuropathy
  Peripheral neuropathy
• UniProt ID: MTMRD_HUMAN
• Pfam ID: PF02141 ; PF02893 ; PF06602 ; PF00169 ; PF12335 ; PF03456
• Sequence:
  MARLADYFIVVGYDHEKPGSGEGLGKIIQRFPQKDWDDTPFPQGIELFCQPGGWQLSRER
  KQPTFFVVVLTDIDSDRHYCSCLTFYEAEINLQGTKKEEIEGEAKVSGLIQPAEVFAPKS
  LVLVSRLYYPEIFRACLGLIYTVYVDSLNVSLESLIANLCACLVPAAGGSQKLFSLGAGD
  RQLIQTPLHDSLPITGTSVALLFQQLGIQNVLSLFCAVLTENKVLFHSASFQRLSDACRA
  LESLMFPLKYSYPYIPILPAQLLEVLSSPTPFIIGVHSVFKTDVHELLDVIIADLDGGTI
  KIPECIHLSSLPEPLLHQTQSALSLILHPDLEVADHAFPPPRTALSHSKMLDKEVRAVFL
  RLFAQLFQGYRSCLQLIRIHAEPVIHFHKTAFLGQRGLVENDFLTKVLSGMAFAGFVSER
  GPPYRSCDLFDELVAFEVERIKVEENNPVKMIKHVRELAEQLFKNENPNPHMAFQKVPRP
  TEGSHLRVHILPFPEINEARVQELIQENVAKNQNAPPATRIEKKCVVPAGPPVVSIMDKV
  TTVFNSAQRLEVVRNCISFIFENKILETEKTLPAALRALKGKAARQCLTDELGLHVQQNR
  AILDHQQFDYIIRMMNCTLQDCSSLEEYNIAAALLPLTSAFYRKLAPGVSQFAYTCVQDH
  PIWTNQQFWETTFYNAVQEQVRSLYLSAKEDNHAPHLKQKDKLPDDHYQEKTAMDLAAEQ
  LRLWPTLSKSTQQELVQHEESTVFSQAIHFANLMVNLLVPLDTSKNKLLRTSAPGDWESG
  SNSIVTNSIAGSVAESYDTESGFEDSENTDIANSVVRFITRFIDKVCTESGVTQDHIKSL
  HCMIPGIVAMHIETLEAVHRESRRLPPIQKPKILRPALLPGEEIVCEGLRVLLDPDGREE
  ATGGLLGGPQLLPAEGALFLTTYRILFRGTPHDQLVGEQTVVRSFPIASITKEKKITMQN
  QLQQNMQEGLQITSASFQLIKVAFDEEVSPEVVEIFKKQLMKFRYPQSIFSTFAFAAGQT
  TPQIILPKQKEKNTSFRTFSKTIVKGAKRAGKMTIGRQYLLKKKTGTIVEERVNRPGWNE
  DDDVSVSDESELPTSTTLKASEKSTMEQLVEKACFRDYQRLGLGTISGSSSRSRPEYFRI
  TASNRMYSLCRSYPGLLVVPQAVQDSSLPRVARCYRHNRLPVVCWKNSRSGTLLLRSGGF
  HGKGVVGLFKSQNSPQAAPTSSLESSSSIEQEKYLQALLNAVSVHQKLRGNSTLTVRPAF
  ALSPGVWASLRSSTRLISSPTSFIDVGARLAGKDHSASFSNSSYLQNQLLKRQAALYIFG
  EKSQLRNFKVEFALNCEFVPVEFHEIRQVKASFKKLMRACIPSTIPTDSEVTFLKALGDS
  EWFPQLHRIMQLAVVVSEVLENGSSVLVCLEEGWDITAQVTSLVQLLSDPFYRTLEGFQM
  LVEKEWLSFGHKFSQRSSLTLNCQGSGFAPVFLQFLDCVHQVHNQYPTEFEFNLYYLKFL
  AFHYVSNRFKTFLLDSDYERLEHGTLFDDKGEKHAKKGVCIWECIDRMHKRSPIFFNYLY
  SPLEIEALKPNVNVSSLKKWDYYIEETLSTGPSYDWMMLTPKHFPSEDSDLAGEAGPRSQ
  RRTVWPCYDDVSCTQPDALTSLFSEIEKLEHKLNQAPEKWQQLWERVTVDLKEEPRTDRS
  QRHLSRSPGIVSTNLPSYQKRSLLHLPDSSMGEEQNSSISPSNGVERRAATLYSQYTSKN
  DENRSFEGTLYKRGALLKGWKPRWFVLDVTKHQLRYYDSGEDTSCKGHIDLAEVEMVIPA
  GPSMGAPKHTSDKAFFDLKTSKRVYNFCAQDGQSAQQWMDKIQSCISDA
• Function: Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. In response to starvation-induced autophagy, activates RAB21 which in turn binds to and regulates SNARE protein VAMP8 endolysosomal transport required for SNARE-mediated autophagosome-lysosome fusion. Acts as an adapter for the phosphatase MTMR2. Increases MTMR2 catalytic activity towards phosphatidylinositol 3,5-bisphosphate and to a lesser extent towards phosphatidylinositol 3-phosphate.
• Tissue Specificity: Widely expressed. Expressed in spinal cord.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease type 1B	DISJRS1V	Definitive	Biomarker	[1]
Charcot-Marie-Tooth disease type 4B1	DISSXR87	Definitive	Biomarker	[2]
Charcot-Marie-Tooth disease type 4B2	DIS7PXQ7	Definitive	Autosomal recessive	[3]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Genetic Variation	[5]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[5]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Griscelli syndrome	DISTHCOQ	Strong	Genetic Variation	[7]
Helicoid peripapillary chorioretinal degeneration	DISFSS5N	Strong	Genetic Variation	[8]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[9]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Genetic Variation	[10]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[11]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[7]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[12]
Hereditary glaucoma	DISJYSR1	Disputed	Genetic Variation	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[14]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[15]
Charcot-Marie-Tooth disease type 4	DISM8IZN	Limited	CausalMutation	[16]
Hereditary motor and sensory neuropathy	DISR0X2K	Limited	Biomarker	[15]
Peripheral neuropathy	DIS7KN5G	Limited	Biomarker	[8]

6 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 Myotubularin-related protein 13 (SBF2).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Myotubularin-related protein 13 (SBF2).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Myotubularin-related protein 13 (SBF2).	[22]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Myotubularin-related protein 13 (SBF2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Myotubularin-related protein 13 (SBF2).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Myotubularin-related protein 13 (SBF2).	[22]

10 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 Myotubularin-related protein 13 (SBF2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myotubularin-related protein 13 (SBF2).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Myotubularin-related protein 13 (SBF2).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Myotubularin-related protein 13 (SBF2).	[23]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Myotubularin-related protein 13 (SBF2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Myotubularin-related protein 13 (SBF2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Myotubularin-related protein 13 (SBF2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Myotubularin-related protein 13 (SBF2).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Myotubularin-related protein 13 (SBF2).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Myotubularin-related protein 13 (SBF2).	[25]

References

• [1] Sural nerve biopsy and functional studies support the pathogenic role of a novel MPZ mutation.Neuropathology. 2015 Jun;35(3):254-9. doi: 10.1111/neup.12179. Epub 2014 Nov 11.
• [2] The CMT4B disease-causing phosphatases Mtmr2 and Mtmr13 localize to the Schwann cell cytoplasm and endomembrane compartments, where they depend upon each other to achieve wild-type levels of protein expression.Hum Mol Genet. 2013 Apr 15;22(8):1493-506. doi: 10.1093/hmg/dds562. Epub 2013 Jan 7.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicing SBF2 (MTMR13) genetic variant: a new spontaneous clinical model.PeerJ. 2019 Nov 21;7:e7983. doi: 10.7717/peerj.7983. eCollection 2019.
• [5] Association analyses identify 31 new risk loci for colorectal cancer susceptibility.Nat Commun. 2019 May 14;10(1):2154. doi: 10.1038/s41467-019-09775-w.
• [6] Upregulated long non-coding RNA SBF2-AS1 promotes proliferation in esophageal squamous cell carcinoma.Oncol Lett. 2018 Apr;15(4):5071-5080. doi: 10.3892/ol.2018.7968. Epub 2018 Feb 6.
• [7] Identification of a novel SBF2 missense mutation associated with a rare case of thrombocytopenia using whole-exome sequencing.J Thromb Thrombolysis. 2013 Nov;36(4):501-6. doi: 10.1007/s11239-012-0864-x.
• [8] Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans.Oncotarget. 2016 Dec 13;7(50):82244-82253. doi: 10.18632/oncotarget.12545.
• [9] Identification of a novel SBF2 frameshift mutation in charcot-marie-tooth disease type 4B2 using whole-exome sequencing.Genomics Proteomics Bioinformatics. 2014 Oct;12(5):221-7. doi: 10.1016/j.gpb.2014.09.003. Epub 2014 Oct 28.
• [10] Genome-wide association study of survival in patients with pancreatic adenocarcinoma.Gut. 2014 Jan;63(1):152-60. doi: 10.1136/gutjnl-2012-303477. Epub 2012 Nov 24.
• [11] Genetic polymorphisms associated with pancreatic cancer survival: a genome-wide association study.Int J Cancer. 2017 Aug 15;141(4):678-686. doi: 10.1002/ijc.30762. Epub 2017 May 15.
• [12] Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.
• [13] Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma. Am J Hum Genet. 2003 May;72(5):1141-53. doi: 10.1086/375034. Epub 2003 Apr 8.
• [14] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [15] Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice.Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4916-21. doi: 10.1073/pnas.0800742105. Epub 2008 Mar 18.
• [16] Charcot-Marie-Tooth 4B2 caused by a novel mutation in the MTMR13/SBF2 gene in two related Portuguese families.Acta Myol. 2014 Dec;33(3):144-8.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [27] 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.
• [28] 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.