Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2EADLC)

• DOT Name: Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3)
• Gene Name: SCUBE3
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Neoplasm
  Renal cell carcinoma
  Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
  Bone osteosarcoma
  Osteosarcoma
• UniProt ID: SCUB3_HUMAN
• Pfam ID: PF12662 ; PF00431 ; PF12947 ; PF07645 ; PF07699 ; PF14670
• Sequence:
  MGSGRVPGLCLLVLLVHARAAQYSKAAQDVDECVEGTDNCHIDAICQNTPRSYKCICKSG
  YTGDGKHCKDVDECEREDNAGCVHDCVNIPGNYRCTCYDGFHLAHDGHNCLDVDECAEGN
  GGCQQSCVNMMGSYECHCREGFFLSDNQHTCIQRPEEGMNCMNKNHGCAHICRETPKGGI
  ACECRPGFELTKNQRDCKLTCNYGNGGCQHTCDDTEQGPRCGCHIKFVLHTDGKTCIETC
  AVNNGGCDSKCHDAATGVHCTCPVGFMLQPDRKTCKDIDECRLNNGGCDHICRNTVGSFE
  CSCKKGYKLLINERNCQDIDECSFDRTCDHICVNTPGSFQCLCHRGYLLYGITHCGDVDE
  CSINRGGCRFGCINTPGSYQCTCPAGQGRLHWNGKDCTEPLKCQGSPGASKAMLSCNRSG
  KKDTCALTCPSRARFLPESENGFTVSCGTPSPRAAPARAGHNGNSTNSNHCHEAAVLSIK
  QRASFKIKDAKCRLHLRNKGKTEEAGRITGPGGAPCSECQVTFIHLKCDSSRKGKGRRAR
  TPPGKEVTRLTLELEAEVRAEETTASCGLPCLRQRMERRLKGSLKMLRKSINQDRFLLRL
  AGLDYELAHKPGLVAGERAEPMESCRPGQHRAGTKCVSCPQGTYYHGQTEQCVPCPAGTF
  QEREGQLSCDLCPGSDAHGPLGATNVTTCAGQCPPGQHSVDGFKPCQPCPRGTYQPEAGR
  TLCFPCGGGLTTKHEGAISFQDCDTKVQCSPGHYYNTSIHRCIRCAMGSYQPDFRQNFCS
  RCPGNTSTDFDGSTSVAQCKNRQCGGELGEFTGYIESPNYPGNYPAGVECIWNINPPPKR
  KILIVVPEIFLPSEDECGDVLVMRKNSSPSSITTYETCQTYERPIAFTARSRKLWINFKT
  SEANSARGFQIPYVTYDEDYEQLVEDIVRDGRLYASENHQEILKDKKLIKAFFEVLAHPQ
  NYFKYTEKHKEMLPKSFIKLLRSKVSSFLRPYK
• Function: Is a positive regulator of the BMP signaling pathway, required for proper chondrogenesis, osteogenesis and skeletal development. It acts as a coreceptor for BMP ligands, particularly BMP2 and BMP4, facilitating their interactions with BMP type I receptors. It is required for ligand-induced recruitment of BMP receptors to lipid rafts. Binds to TGFBR2 and activates TGFB signaling. In lung cancer cells, could serve as an endogenous autocrine and paracrine ligand of TGFBR2, which could regulate TGFBR2 signaling and hence modulate epithelial-mesenchymal transition and cancer progression.
• Tissue Specificity: Highly expressed in osteoblasts. In normal lung, mainly expressed in bronchial epithelial cells. Tends to be up-regulated in lung cancer cells.
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[1]
Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2	DIS752NN	Strong	Autosomal recessive	[2]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[3]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[10]

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 Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Signal peptide, CUB and EGF-like domain-containing protein 3 (SCUBE3).	[8]

References

• [1] Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma.Oncogene. 2011 Mar 24;30(12):1390-401. doi: 10.1038/onc.2010.525. Epub 2010 Dec 6.
• [2] The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations. G3 (Bethesda). 2016 Dec 7;6(12):4035-4046. doi: 10.1534/g3.116.033670.
• [3] The Expression of HSPD1, SCUBE3, CXCL14 and Its Relations with the Prognosis in Osteosarcoma.Cell Biochem Biophys. 2015 Dec;73(3):763-8. doi: 10.1007/s12013-015-0579-7.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [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] 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.
• [9] 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.
• [10] 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.