Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8EFJPM)

• DOT Name: APC membrane recruitment protein 1 (AMER1)
• Synonyms: Amer1; Protein FAM123B; Wilms tumor gene on the X chromosome protein
• Gene Name: AMER1
• Related Disease:
  Osteopathia striata with cranial sclerosis
  Advanced cancer
  Anal intraepithelial neoplasia
  Beckwith-Wiedemann syndrome
  Bone disease
  Colorectal carcinoma
  Familial adenomatous polyposis
  Hepatocellular carcinoma
  Hyperostosis
  Kidney cancer
  Neoplasm
  Osteochondrodysplasia
  Renal carcinoma
  Skeletal dysplasia
  Malignant soft tissue neoplasm
  Sarcoma
  Intellectual disability
  Acute myelogenous leukaemia
• UniProt ID: AMER1_HUMAN
• PDB ID: 4YJE; 4YJL; 4YK6
• Pfam ID: PF09422
• Sequence:
  METQKDEAAQAKGAAASGSTREQTAEKGAKNKAAEATEGPTSEPSSSGPGRLKKTAMKLF
  GGKKGICTLPSFFGGGRSKGSGKGSSKKGLSKSKTHDGLSEAAHGPEDVVSEGTGFSLPL
  PELPCQFPSSQSAHGALETGSRCKTSVAGATEKAVAEKFPSMPKPKKGLKGFFSSIRRHR
  KSKVTGAEQSEPGAKGPERVRARPHEHVSSAPQVPCFEETFQAPRKENANPQDAPGPKVS
  PTPEPSPPATEKMACKDPEKPMEACASAHVQPKPAPEASSLEEPHSPETGEKVVAGEVNP
  PNGPVGDPLSLLFGDVTSLKSFDSLTGCGDIIAEQDMDSMTDSMASGGQRANRDGTKRSS
  CLVTYQGGGEEMALPDDDDEEEEEEEEVELEEEEEEVKEEEEDDDLEYLWETAQMYPRPN
  MNLGYHPTTSPGHHGYMLLDPVRSYPGLAPGELLTPQSDQQESAPNSDEGYYDSTTPGFE
  DDSGEALGLVRRDCLPRDSYSGDALYEFYEPDDSLENSPPGDDCLYDLHGRSSEMFDPFL
  NFEPFLSSRPPGAMETEEERLVTIQKQLLYWELRREQLEAQEARAREAHAREAHAREAYT
  REAYGREAYAREAHTWEAHGREARTREAQAREVRCRETQVRETQARQEKPVLEYQMRPLG
  PSVMGLAAGVSGTSQISHRGITSAFPTTASSEPDWRDFRPLEKRYEGTCSKKDQSTCLMQ
  LFQSDAMFEPDMQEANFGGSPRRAYPTYSPPEDPEEEEVEKEGNATVSFSQALVEFTSNG
  NLFSSMSCSSDSDSSFTQNLPELPPMVTFDIADVERDGEGKCEENPEFHNDEDLAASLEA
  FELGYYHKHAFNNYHSRFYQGLPWGVSSLPRYLGLPGLHPRPPPAAMALNRRSRSLDTAE
  TLEMELSNSHLVQGYLESDELQAQQEDSDEEDEEEEEGEWSRDSPLSLYTEPPGAYDWPA
  WAPCPLPVGPGPAWISPNQLDRPSSQSPYRQATCCIPPMTMSISLSVPESRAPGESGPQL
  ARPSHLHLPMGPCYNLQPQASQSMRARPRDVLLPVDEPSCSSSSGGFSPSPLPQAKPVGI
  THGIPQLPRVRPEHPQPQPTHYGPSSLDLSKERAEQGASLATSYSSTAMNGNLAK
• Function: Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.
• Tissue Specificity: Detected in fetal and adult kidney, brain and spleen.
• Reactome Pathway:
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Signaling by GSK3beta mutants (R-HSA-5339716)
  CTNNB1 S33 mutants aren't phosphorylated (R-HSA-5358747)
  CTNNB1 S37 mutants aren't phosphorylated (R-HSA-5358749)
  CTNNB1 S45 mutants aren't phosphorylated (R-HSA-5358751)
  CTNNB1 T41 mutants aren't phosphorylated (R-HSA-5358752)
  APC truncation mutants have impaired AXIN binding (R-HSA-5467337)
  AXIN missense mutants destabilize the destruction complex (R-HSA-5467340)
  Truncations of AMER1 destabilize the destruction complex (R-HSA-5467348)
  Neddylation (R-HSA-8951664)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteopathia striata with cranial sclerosis	DISEC815	Definitive	X-linked	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Biomarker	[3]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Genetic Variation	[4]
Bone disease	DISE1F82	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[8]
Hyperostosis	DIS60EOE	Strong	Biomarker	[9]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[11]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[12]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[10]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[12]
Malignant soft tissue neoplasm	DISTC6NO	moderate	Biomarker	[2]
Sarcoma	DISZDG3U	moderate	Biomarker	[2]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[13]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of APC membrane recruitment protein 1 (AMER1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of APC membrane recruitment protein 1 (AMER1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of APC membrane recruitment protein 1 (AMER1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of APC membrane recruitment protein 1 (AMER1).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of APC membrane recruitment protein 1 (AMER1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of APC membrane recruitment protein 1 (AMER1).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of APC membrane recruitment protein 1 (AMER1).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of APC membrane recruitment protein 1 (AMER1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of APC membrane recruitment protein 1 (AMER1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of APC membrane recruitment protein 1 (AMER1).	[23]

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] Inactivation of the tumor suppressor WTX in a subset of pediatric tumors.Genes Chromosomes Cancer. 2014 Jan;53(1):67-77. doi: 10.1002/gcc.22118. Epub 2013 Nov 5.
• [3] LMP1 antagonizes WNT/-catenin signalling through inhibition of WTX and promotes nasopharyngeal dysplasia but not tumourigenesis in LMP1(B95-8) transgenic mice.J Pathol. 2011 Apr;223(5):574-83. doi: 10.1002/path.2820. Epub 2010 Dec 10.
• [4] Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers.Clin Cancer Res. 2010 Nov 1;16(21):5133-41. doi: 10.1158/1078-0432.CCR-10-1497. Epub 2010 Oct 26.
• [5] Zebrafish Wtx is a negative regulator of Wnt signaling but is dispensable for embryonic development and organ homeostasis.Dev Dyn. 2019 Sep;248(9):866-881. doi: 10.1002/dvdy.84. Epub 2019 Jul 27.
• [6] Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer.Clin Cancer Res. 2015 Oct 15;21(20):4709-18. doi: 10.1158/1078-0432.CCR-15-0159. Epub 2015 Jun 12.
• [7] Adenomatous polyposis coli (APC) membrane recruitment 3, a member of the APC membrane recruitment family of APC-binding proteins, is a positive regulator of Wnt--catenin signalling.FEBS J. 2014 Feb;281(3):787-801. doi: 10.1111/febs.12624. Epub 2013 Dec 12.
• [8] Mutational analysis of WTX gene in Wnt/ beta-catenin pathway in gastric, colorectal, and hepatocellular carcinomas.Dig Dis Sci. 2009 May;54(5):1011-4. doi: 10.1007/s10620-008-0458-9. Epub 2008 Aug 22.
• [9] Severe osteopathia striata with cranial sclerosis in a female case with whole WTX gene deletion.Am J Med Genet A. 2013 Mar;161A(3):594-9. doi: 10.1002/ajmg.a.35716. Epub 2013 Feb 7.
• [10] Genetic and Molecular Insights Into Genotype-Phenotype Relationships in Osteopathia Striata With Cranial Sclerosis (OSCS) Through the Analysis of Novel Mouse Wtx Mutant Alleles.J Bone Miner Res. 2018 May;33(5):875-887. doi: 10.1002/jbmr.3387. Epub 2018 Mar 1.
• [11] Clinical, Pathologic, and Genetic Features of Wilms Tumors With WTX Gene Mutation.Pediatr Dev Pathol. 2017 Mar-Apr;20(2):105-111. doi: 10.1177/1093526616683881. Epub 2017 Jan 26.
• [12] Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet. 2009 Jan;41(1):95-100. doi: 10.1038/ng.270. Epub 2008 Dec 14.
• [13] Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus.Clin Genet. 2013 Mar;83(3):251-6. doi: 10.1111/j.1399-0004.2012.01905.x. Epub 2012 Jul 5.
• [14] WTX is rarely mutated in acute myeloid leukemia.Haematologica. 2008 Jun;93(6):947-8. doi: 10.3324/haematol.12509. Epub 2008 May 6.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.