Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT46DZXJ)

• DOT Name: Protein Cripto (CRIPTO)
• Synonyms: Cripto, EGF-CFC family member; Cripto-1 growth factor; CRGF; Epidermal growth factor-like cripto protein CR1; Teratocarcinoma-derived growth factor 1
• Gene Name: CRIPTO
• UniProt ID: TDGF1_HUMAN
• Pfam ID: PF09443
• Sequence:
  MDCRKMARFSYSVIWIMAISKVFELGLVAGLGHQEFARPSRGYLAFRDDSIWPQEEPAIR
  PRSSQRVPPMGIQHSKELNRTCCLNGGTCMLGSFCACPPSFYGRNCEHDVRKENCGSVPH
  DTWLPKKCSLCKCWHGQLRCFPQAFLPGCDGLVMDEHLVASRTPELPPSARTTTFMLVGI
  CLSIQSYY
• Function: GPI-anchored cell membrane protein involved in Nodal signaling. Cell-associated CRIPTO acts as a Nodal coreceptor in cis. Shedding of CRIPTO by TMEM8A modulates Nodal signaling by allowing soluble CRIPTO to act as a Nodal coreceptor on other cells. Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm.
• Tissue Specificity: Preferentially expressed in gastric and colorectal carcinomas than in their normal counterparts. Expressed in breast and lung.
• Reactome Pathway:
  Regulation of signaling by NODAL (R-HSA-1433617)
  POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation (R-HSA-2892247)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Protein Cripto (CRIPTO).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Cripto (CRIPTO).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein Cripto (CRIPTO).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein Cripto (CRIPTO).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein Cripto (CRIPTO).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein Cripto (CRIPTO).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Protein Cripto (CRIPTO).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein Cripto (CRIPTO).	[5]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Protein Cripto (CRIPTO).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein Cripto (CRIPTO).	[9]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Protein Cripto (CRIPTO).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein Cripto (CRIPTO).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein Cripto (CRIPTO).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protein Cripto (CRIPTO).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein Cripto (CRIPTO).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein Cripto (CRIPTO).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Cripto (CRIPTO).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein Cripto (CRIPTO).	[5]

References

• [1] 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.
• [2] Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3. J Biol Chem. 2006 Nov 3;281(44):33497-504. doi: 10.1074/jbc.M606975200. Epub 2006 Sep 5.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [8] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [9] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [10] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.