Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE91EWT)

• DOT Name: Gremlin-2 (GREM2)
• Synonyms: Cysteine knot superfamily 1, BMP antagonist 2; DAN domain family member 3; Protein related to DAN and cerberus
• Gene Name: GREM2
• Related Disease:
  Alzheimer disease
  Atrial fibrillation
  Diabetic kidney disease
  Myocardial infarction
  Osteoporosis
  Tooth agenesis
  Polycystic ovarian syndrome
  Neoplasm
  Gastric cancer
  Stomach cancer
• UniProt ID: GREM2_HUMAN
• Pfam ID: PF03045
• Sequence:
  MFWKLSLSLFLVAVLVKVAEARKNRPAGAIPSPYKDGSSNNSERWQHQIKEVLASSQEAL
  VVTERKYLKSDWCKTQPLRQTVSEEGCRSRTILNRFCYGQCNSFYIPRHVKKEEESFQSC
  AFCKPQRVTSVLVELECPGLDPPFRLKKIQKVKQCRCMSVNLSDSDKQ
• Function: Cytokine that inhibits the activity of BMP2 and BMP4 in a dose-dependent manner, and thereby modulates signaling by BMP family members. Contributes to the regulation of embryonic morphogenesis via BMP family members. Antagonizes BMP4-induced suppression of progesterone production in granulosa cells.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway: Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[3]
Myocardial infarction	DIS655KI	Strong	Biomarker	[4]
Osteoporosis	DISF2JE0	Strong	Biomarker	[5]
Tooth agenesis	DIS1PWC7	Strong	Genetic Variation	[6]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Altered Expression	[7]
Neoplasm	DISZKGEW	Disputed	Genetic Variation	[8]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[9]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[9]

3 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 Gremlin-2 (GREM2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gremlin-2 (GREM2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Gremlin-2 (GREM2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gremlin-2 (GREM2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gremlin-2 (GREM2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gremlin-2 (GREM2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Gremlin-2 (GREM2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gremlin-2 (GREM2).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Gremlin-2 (GREM2).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Gremlin-2 (GREM2).	[17]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Gremlin-2 (GREM2).	[18]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Gremlin-2 (GREM2).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gremlin-2 (GREM2).	[14]

References

• [1] Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease.Mol Psychiatry. 2013 May;18(5):568-75. doi: 10.1038/mp.2012.81. Epub 2012 Jun 19.
• [2] Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm.Dis Model Mech. 2013 Mar;6(2):332-41. doi: 10.1242/dmm.010488. Epub 2012 Dec 7.
• [3] Grem2 mediates podocyte apoptosis in high glucose milieu.Biochimie. 2019 May;160:113-121. doi: 10.1016/j.biochi.2019.02.015. Epub 2019 Mar 1.
• [4] Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway.Cell Physiol Biochem. 2018;47(2):579-589. doi: 10.1159/000490012. Epub 2018 May 22.
• [5] Genetic variants in GREM2 are associated with bone mineral density in a southern Chinese population.J Clin Endocrinol Metab. 2013 Sep;98(9):E1557-61. doi: 10.1210/jc.2013-1983. Epub 2013 Jul 31.
• [6] GREM2 nucleotide variants and the risk of tooth agenesis.Oral Dis. 2018 May;24(4):591-599. doi: 10.1111/odi.12793. Epub 2017 Nov 3.
• [7] Gremlin-1 and gremlin-2 levels in polycystic ovary syndrome and their clinical correlations.Gynecol Endocrinol. 2019 Jul;35(7):604-607. doi: 10.1080/09513590.2019.1566452. Epub 2019 Feb 4.
• [8] Target genes of the WNT/beta-catenin pathway in Wilms tumors.Genes Chromosomes Cancer. 2006 Jun;45(6):565-74. doi: 10.1002/gcc.20319.
• [9] GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway.Cell Cycle. 2019 Oct;18(19):2414-2431. doi: 10.1080/15384101.2019.1646561. Epub 2019 Aug 25.
• [10] 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.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [18] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [19] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [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] 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.