Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT209XLA)

• DOT Name: Activin receptor type-2B (ACVR2B)
• Synonyms: EC 2.7.11.30; Activin receptor type IIB; ACTR-IIB
• Gene Name: ACVR2B
• Related Disease: Heterotaxy, visceral, 4, autosomal
• UniProt ID: AVR2B_HUMAN
• PDB ID: 2H62; 2QLU; 4FAO; 5NGV; 5NHR; 7MRZ; 7OLY
• EC Number: 2.7.11.30
• Pfam ID: PF01064 ; PF00069
• Sequence:
  MTAPWVALALLWGSLCAGSGRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCY
  ASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAG
  GPEVTYEPPPTAPTLLTVLAYSLLPIGGLSLIVLLAFWMYRHRKPPYGHVDIHEDPGPPP
  PSPLVGLKPLQLLEIKARGRFGCVWKAQLMNDFVAVKIFPLQDKQSWQSEREIFSTPGMK
  HENLLQFIAAEKRGSNLEVELWLITAFHDKGSLTDYLKGNIITWNELCHVAETMSRGLSY
  LHEDVPWCRGEGHKPSIAHRDFKSKNVLLKSDLTAVLADFGLAVRFEPGKPPGDTHGQVG
  TRRYMAPEVLEGAINFQRDAFLRIDMYAMGLVLWELVSRCKAADGPVDEYMLPFEEEIGQ
  HPSLEELQEVVVHKKMRPTIKDHWLKHPGLAQLCVTIEECWDHDAEARLSAGCVEERVSL
  IRRSVNGTTSDCLVSLVTSVTNVDLPPKESSI
• Function: Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). The type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Regulation of signaling by NODAL (R-HSA-1433617)
  Signaling by Activin (R-HSA-1502540)
  Signaling by BMP (R-HSA-201451)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Heterotaxy, visceral, 4, autosomal	DIS1HP9X	Strong	Autosomal dominant	[1]

15 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 Activin receptor type-2B (ACVR2B).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Activin receptor type-2B (ACVR2B).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Activin receptor type-2B (ACVR2B).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Activin receptor type-2B (ACVR2B).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Activin receptor type-2B (ACVR2B).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Activin receptor type-2B (ACVR2B).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Activin receptor type-2B (ACVR2B).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Activin receptor type-2B (ACVR2B).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Activin receptor type-2B (ACVR2B).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Activin receptor type-2B (ACVR2B).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Activin receptor type-2B (ACVR2B).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Activin receptor type-2B (ACVR2B).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Activin receptor type-2B (ACVR2B).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Activin receptor type-2B (ACVR2B).	[13]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Activin receptor type-2B (ACVR2B).	[14]

References

• [1] Mutations in ZIC3 and ACVR2B are a common cause of heterotaxy and associated cardiovascular anomalies. Cardiol Young. 2012 Apr;22(2):194-201. doi: 10.1017/S1047951111001181. Epub 2011 Aug 25.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] BMP7/ActRIIB regulates estrogen-dependent apoptosis: new biomarkers for environmental estrogens. J Biochem Mol Toxicol. 2004;18(1):1-11. doi: 10.1002/jbt.20004.
• [7] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [8] 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.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.