Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWS8WSW)

• DOT Name: Glypican-3 (GPC3)
• Synonyms: GTR2-2; Intestinal protein OCI-5; MXR7
• Gene Name: GPC3
• Related Disease:
  Simpson-Golabi-Behmel syndrome
  Simpson-Golabi-Behmel syndrome type 1
• UniProt ID: GPC3_HUMAN
• PDB ID: 7ZA1; 7ZAW
• Pfam ID: PF01153
• Sequence:
  MAGTVRTACLVVAMLLSLDFPGQAQPPPPPPDATCHQVRSFFQRLQPGLKWVPETPVPGS
  DLQVCLPKGPTCCSRKMEEKYQLTARLNMEQLLQSASMELKFLIIQNAAVFQEAFEIVVR
  HAKNYTNAMFKNNYPSLTPQAFEFVGEFFTDVSLYILGSDINVDDMVNELFDSLFPVIYT
  QLMNPGLPDSALDINECLRGARRDLKVFGNFPKLIMTQVSKSLQVTRIFLQALNLGIEVI
  NTTDHLKFSKDCGRMLTRMWYCSYCQGLMMVKPCGGYCNVVMQGCMAGVVEIDKYWREYI
  LSLEELVNGMYRIYDMENVLLGLFSTIHDSIQYVQKNAGKLTTTIGKLCAHSQQRQYRSA
  YYPEDLFIDKKVLKVAHVEHEETLSSRRRELIQKLKSFISFYSALPGYICSHSPVAENDT
  LCWNGQELVERYSQKAARNGMKNQFNLHELKMKGPEPVVSQIIDKLKHINQLLRTMSMPK
  GRVLDKNLDEEGFESGDCGDDEDECIGGSGDGMIKVKNQLRFLAELAYDLDVDDAPGNSQ
  QATPKDNEISTFHNLGNVHSPLKLLTSMAISVVCFFFLVH
• Function: Cell surface proteoglycan. Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins. Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation. Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands. Positively regulates the non-canonical Wnt signaling pathway. Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression. Inhibits the dipeptidyl peptidase activity of DPP4. Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4. Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis. Required for coronary vascular development. Plays a role in regulating cell movements during gastrulation.
• Tissue Specificity: Detected in placenta (at protein level) . Highly expressed in lung, liver and kidney.
• KEGG Pathway: Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  HS-GAG biosynthesis (R-HSA-2022928)
  HS-GAG degradation (R-HSA-2024096)
  Defective B4GALT7 causes EDS, progeroid type (R-HSA-3560783)
  Defective B3GAT3 causes JDSSDHD (R-HSA-3560801)
  Defective EXT2 causes exostoses 2 (R-HSA-3656237)
  Defective EXT1 causes exostoses 1, TRPS2 and CHDS (R-HSA-3656253)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Defective B3GALT6 causes EDSP2 and SEMDJL1 (R-HSA-4420332)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Attachment and Entry (R-HSA-9694614)
  Retinoid metabolism and transport (R-HSA-975634)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Simpson-Golabi-Behmel syndrome	DIS9H9TY	Definitive	X-linked	[1]
Simpson-Golabi-Behmel syndrome type 1	DISYV73N	Definitive	X-linked	[2]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Glypican-3 (GPC3) increases the response to substance of Doxorubicin.	[15]
Cisplatin	DMRHGI9	Approved	Glypican-3 (GPC3) increases the response to substance of Cisplatin.	[15]
Methotrexate	DM2TEOL	Approved	Glypican-3 (GPC3) increases the response to substance of Methotrexate.	[15]
Paclitaxel	DMLB81S	Approved	Glypican-3 (GPC3) increases the response to substance of Paclitaxel.	[15]
Topotecan	DMP6G8T	Approved	Glypican-3 (GPC3) increases the response to substance of Topotecan.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glypican-3 (GPC3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glypican-3 (GPC3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Glypican-3 (GPC3).	[13]

11 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 Glypican-3 (GPC3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glypican-3 (GPC3).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Glypican-3 (GPC3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Glypican-3 (GPC3).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glypican-3 (GPC3).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Glypican-3 (GPC3).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Glypican-3 (GPC3).	[7]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glypican-3 (GPC3).	[10]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Glypican-3 (GPC3).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glypican-3 (GPC3).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glypican-3 (GPC3).	[14]

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] Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet. 1996 Mar;12(3):241-7. doi: 10.1038/ng0396-241.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically. Clin Transl Med. 2021 Feb;11(2):e335. doi: 10.1002/ctm2.335.
• [7] 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.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Microarray-based detection and expression analysis of extracellular matrix proteins in drug?resistant ovarian cancer cell lines. Oncol Rep. 2014 Nov;32(5):1981-90. doi: 10.3892/or.2014.3468. Epub 2014 Sep 9.