Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT67CC7W)

• DOT Name: Membrane-bound transcription factor site-2 protease (MBTPS2)
• Synonyms: EC 3.4.24.85; Endopeptidase S2P; Sterol regulatory element-binding proteins intramembrane protease; SREBPs intramembrane protease
• Gene Name: MBTPS2
• Related Disease:
  IFAP syndrome 1, with or without BRESHECK syndrome
  Advanced cancer
  Alopecia
  Castration-resistant prostate carcinoma
  Chromosomal disorder
  Classic Hodgkin lymphoma
  Coffin-Lowry syndrome
  Cryptococcosis
  Folliculitis
  Keratosis pilaris
  Liposarcoma
  Non-alcoholic fatty liver disease
  Non-syndromic ichthyosis
  Osteogenesis imperfecta, type 19
  Renal dysplasia
  Intellectual disability
  BRESEK syndrome
  Keratosis follicularis spinulosa decalvans
  Obsolete mutilating palmoplantar keratoderma with periorificial keratotic plaques
  Osteogenesis imperfecta
  Corneal dystrophy
  Hepatocellular carcinoma
  IFAP syndrome
  Keratosis follicularis spinulosa decalvans, X-linked
  Olmsted syndrome, X-linked
  Polydactyly
  Polyposis
• UniProt ID: MBTP2_HUMAN
• EC Number: 3.4.24.85
• Pfam ID: PF02163
• Sequence:
  MIPVSLVVVVVGGWTVVYLTDLVLKSSVYFKHSYEDWLENNGLSISPFHIRWQTAVFNRA
  FYSWGRRKARMLYQWFNFGMVFGVIAMFSSFFLLGKTLMQTLAQMMADSPSSYSSSSSSS
  SSSSSSSSSSSSSSSSLHNEQVLQVVVPGINLPVNQLTYFFTAVLISGVVHEIGHGIAAI
  REQVRFNGFGIFLFIIYPGAFVDLFTTHLQLISPVQQLRIFCAGIWHNFVLALLGILALV
  LLPVILLPFYYTGVGVLITEVAEDSPAIGPRGLFVGDLVTHLQDCPVTNVQDWNECLDTI
  AYEPQIGYCISASTLQQLSFPVRAYKRLDGSTECCNNHSLTDVCFSYRNNFNKRLHTCLP
  ARKAVEATQVCRTNKDCKKSSSSSFCIIPSLETHTRLIKVKHPPQIDMLYVGHPLHLHYT
  VSITSFIPRFNFLSIDLPVVVETFVKYLISLSGALAIVNAVPCFALDGQWILNSFLDATL
  TSVIGDNDVKDLIGFFILLGGSVLLAANVTLGLWMVTAR
• Function: Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2. Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached. Mature N-terminal SREBP fragments shuttle to the nucleus and activate gene transcription. Also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B). Involved in intramembrane proteolysis during bone formation. In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the second step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  ATF6 (ATF6-alpha) activates chaperones (R-HSA-381033)
  ATF6B (ATF6-beta) activates chaperones (R-HSA-8874177)
  CREB3 factors activate genes (R-HSA-8874211)
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Regulation of cholesterol biosynthesis by SREBP (SREBF) (R-HSA-1655829)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
IFAP syndrome 1, with or without BRESHECK syndrome	DISDNKAH	Definitive	X-linked	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alopecia	DIS37HU4	Strong	Biomarker	[3]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[6]
Coffin-Lowry syndrome	DISMTBDA	Strong	Biomarker	[7]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[8]
Folliculitis	DIS10XOM	Strong	Biomarker	[9]
Keratosis pilaris	DISKOBPU	Strong	Biomarker	[10]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[11]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Genetic Variation	[12]
Osteogenesis imperfecta, type 19	DISV3Q10	Strong	X-linked	[13]
Renal dysplasia	DIS3DFGD	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[14]
BRESEK syndrome	DISANNCT	Supportive	X-linked	[14]
Keratosis follicularis spinulosa decalvans	DIS2MNKW	Supportive	Autosomal dominant	[15]
Obsolete mutilating palmoplantar keratoderma with periorificial keratotic plaques	DIST2Y4B	Supportive	Autosomal dominant	[16]
Osteogenesis imperfecta	DIS7XQSD	Supportive	Autosomal dominant	[13]
Corneal dystrophy	DISRDPA6	Limited	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[18]
IFAP syndrome	DISCHYO2	Limited	Genetic Variation	[19]
Keratosis follicularis spinulosa decalvans, X-linked	DIS4297N	Limited	X-linked	[20]
Olmsted syndrome, X-linked	DISXH2KM	Limited	X-linked	[20]
Polydactyly	DIS25BMZ	Limited	Biomarker	[21]
Polyposis	DISZSPOK	Limited	Genetic Variation	[22]

2 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 Membrane-bound transcription factor site-2 protease (MBTPS2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Membrane-bound transcription factor site-2 protease (MBTPS2).	[28]

5 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 Membrane-bound transcription factor site-2 protease (MBTPS2).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Membrane-bound transcription factor site-2 protease (MBTPS2).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Membrane-bound transcription factor site-2 protease (MBTPS2).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Membrane-bound transcription factor site-2 protease (MBTPS2).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Membrane-bound transcription factor site-2 protease (MBTPS2).	[29]

References

• [1] 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.
• [2] Nelfinavir induces liposarcoma apoptosis through inhibition of regulated intramembrane proteolysis of SREBP-1 and ATF6. Clin Cancer Res. 2011 Apr 1;17(7):1796-806. doi: 10.1158/1078-0432.CCR-10-3216. Epub 2011 Feb 25.
• [3] Novel MBTPS2 missense mutation causes a keratosis follicularis spinulosa decalvans phenotype: mutation update and review of the literature.Clin Exp Dermatol. 2016 Oct;41(7):757-60. doi: 10.1111/ced.12889.
• [4] Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer.FEBS J. 2012 Jul;279(13):2399-411. doi: 10.1111/j.1742-4658.2012.08619.x. Epub 2012 May 21.
• [5] Linkage analysis of keratosis follicularis spinulosa decalvans, and regional assignment to human chromosome Xp21.2-p22.2.Am J Hum Genet. 1992 Apr;50(4):801-7.
• [6] Hodgkin Lymphoma in a Patient With IFAP Syndrome: A Case Report and Review of Literature.J Pediatr Hematol Oncol. 2018 Apr;40(3):227-230. doi: 10.1097/MPH.0000000000000894.
• [7] High-resolution mapping by YAC fragmentation of a 2.5-Mb Xp22 region containing the human RS, KFSD and CLS disease genes.Mamm Genome. 1997 Jul;8(7):497-501. doi: 10.1007/s003359900483.
• [8] Cryptococcus neoformans Site-2 protease is required for virulence and survival in the presence of azole drugs.Mol Microbiol. 2009 Nov;74(3):672-90. doi: 10.1111/j.1365-2958.2009.06895.x. Epub 2009 Oct 8.
• [9] Keratosis follicularis spinulosa decalvans associated with acne keloidalis nuchae and tufted hair folliculitis.Am J Clin Dermatol. 2008;9(2):137-40. doi: 10.2165/00128071-200809020-00009.
• [10] MBTPS2 mutation in a British pedigree with keratosis follicularis spinulosa decalvans.Clin Exp Dermatol. 2012 Aug;37(6):631-4. doi: 10.1111/j.1365-2230.2011.04288.x.
• [11] Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD.Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Mar;1862(3):337-350. doi: 10.1016/j.bbalip.2016.12.007. Epub 2016 Dec 21.
• [12] Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient.Clin Exp Dermatol. 2014 Mar;39(2):158-61. doi: 10.1111/ced.12248. Epub 2013 Dec 7.
• [13] MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun. 2016 Jul 6;7:11920. doi: 10.1038/ncomms11920.
• [14] MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A. 2012 Jan;158A(1):97-102. doi: 10.1002/ajmg.a.34373. Epub 2011 Nov 21.
• [15] Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2. Hum Mutat. 2010 Oct;31(10):1125-33. doi: 10.1002/humu.21335.
• [16] A missense mutation in the MBTPS2 gene underlies the X-linked form of Olmsted syndrome. J Invest Dermatol. 2013 Feb;133(2):571-3. doi: 10.1038/jid.2012.289. Epub 2012 Aug 30.
• [17] Keratosis follicularis spinulosa decalvans: a family study of seven male cases and six female carriers.J Med Genet. 1992 Jan;29(1):36-40. doi: 10.1136/jmg.29.1.36.
• [18] Dietary alpha-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells.J Lipid Res. 2004 Feb;45(2):308-16. doi: 10.1194/jlr.M300396-JLR200. Epub 2003 Oct 16.
• [19] Ichthyosis follicularis, atrichia, and photophobia syndrome associated with a new mutation in MBTPS2.Clin Exp Dermatol. 2015 Jul;40(5):529-32. doi: 10.1111/ced.12587. Epub 2015 Feb 16.
• [20] 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.
• [21] Brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia (BRESEK/BRESHECK): new X-linked syndrome?.Am J Med Genet. 1997 Feb 11;68(4):386-90. doi: 10.1002/(sici)1096-8628(19970211)68:4<386::aid-ajmg2>3.0.co;2-k.
• [22] Characterization of APC exon 15 germ-line mutation in FAP family with severe phenotype showing extracolonic symptoms.Neoplasma. 1999;46(5):290-4.
• [23] 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.
• [24] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [25] 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.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [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] 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.