Details of Drug Off-Target (DOT)

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

• DOT Name: Activin receptor type-1C (ACVR1C)
• Synonyms: EC 2.7.11.30; Activin receptor type IC; ACTR-IC; Activin receptor-like kinase 7; ALK-7
• Gene Name: ACVR1C
• Related Disease:
  Metabolic disorder
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Diabetic retinopathy
  Dilated cardiomyopathy 1A
  Ductal breast carcinoma in situ
  Epithelial ovarian cancer
  Invasive ductal breast carcinoma
  Matthew-Wood syndrome
  Non-insulin dependent diabetes
  Ovarian cancer
  Ovarian neoplasm
  Retinoblastoma
  Neoplasm
  Obesity
• UniProt ID: ACV1C_HUMAN
• EC Number: 2.7.11.30
• Pfam ID: PF01064 ; PF07714 ; PF08515
• Sequence:
  MTRALCSALRQALLLLAAAAELSPGLKCVCLLCDSSNFTCQTEGACWASVMLTNGKEQVI
  KSCVSLPELNAQVFCHSSNNVTKTECCFTDFCNNITLHLPTASPNAPKLGPMELAIIITV
  PVCLLSIAAMLTVWACQGRQCSYRKKKRPNVEEPLSECNLVNAGKTLKDLIYDVTASGSG
  SGLPLLVQRTIARTIVLQEIVGKGRFGEVWHGRWCGEDVAVKIFSSRDERSWFREAEIYQ
  TVMLRHENILGFIAADNKDNGTWTQLWLVSEYHEQGSLYDYLNRNIVTVAGMIKLALSIA
  SGLAHLHMEIVGTQGKPAIAHRDIKSKNILVKKCETCAIADLGLAVKHDSILNTIDIPQN
  PKVGTKRYMAPEMLDDTMNVNIFESFKRADIYSVGLVYWEIARRCSVGGIVEEYQLPYYD
  MVPSDPSIEEMRKVVCDQKFRPSIPNQWQSCEALRVMGRIMRECWYANGAARLTALRIKK
  TISQLCVKEDCKA
• Function: Serine/threonine protein kinase which forms a receptor complex on ligand binding. The receptor complex consisting of 2 type II and 2 type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators, SMAD2 and SMAD3. Receptor for activin AB, activin B and NODAL. Plays a role in cell differentiation, growth arrest and apoptosis.
• Tissue Specificity: Present in pancreas, heart, colon, small intestine, ovary and the hippocampus, medulla oblongata and putamen of the brain. Isoform 1, isoform 2, isoform 3 and isoform 4 are all expressed in the placenta throughout pregnancy.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Regulation of signaling by NODAL (R-HSA-1433617)
  Signaling by Activin (R-HSA-1502540)
  Signaling by NODAL (R-HSA-1181150)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Obesity	DIS47Y1K	Limited	Biomarker	[10]

1 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 Activin receptor type-1C (ACVR1C).	[11]

10 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 Activin receptor type-1C (ACVR1C).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Activin receptor type-1C (ACVR1C).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Activin receptor type-1C (ACVR1C).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Activin receptor type-1C (ACVR1C).	[15]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Activin receptor type-1C (ACVR1C).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Activin receptor type-1C (ACVR1C).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Activin receptor type-1C (ACVR1C).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Activin receptor type-1C (ACVR1C).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Activin receptor type-1C (ACVR1C).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Activin receptor type-1C (ACVR1C).	[21]

References

• [1] ALK7 expression is specific for adipose tissue, reduced in obesity and correlates to factors implicated in metabolic disease.Biochem Biophys Res Commun. 2009 May 1;382(2):309-14. doi: 10.1016/j.bbrc.2009.03.014. Epub 2009 Mar 9.
• [2] Overexpression of Activin Receptor-like Kinase 7 in Breast Cancer Cells Is Associated with Decreased Cell Growth and Adhesion.Anticancer Res. 2017 Jul;37(7):3441-3451. doi: 10.21873/anticanres.11712.
• [3] ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis.Dev Cell. 2019 May 6;49(3):409-424.e6. doi: 10.1016/j.devcel.2019.04.015.
• [4] Knockdown of ALK7 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells.Clin Exp Pharmacol Physiol. 2020 Feb;47(2):313-321. doi: 10.1111/1440-1681.13189. Epub 2019 Nov 19.
• [5] Reduced expression of activin receptor-like kinase 7 in breast cancer is associated with tumor progression.Med Oncol. 2012 Dec;29(4):2519-26. doi: 10.1007/s12032-011-0114-7. Epub 2011 Nov 16.
• [6] MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance. J Cell Sci. 2011 Feb 1;124(Pt 3):359-68. doi: 10.1242/jcs.072223. Epub 2011 Jan 11.
• [7] A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling.Sci Adv. 2019 Aug 28;5(8):eaav6789. doi: 10.1126/sciadv.aav6789. eCollection 2019 Aug.
• [8] DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes.Diabetes. 2019 Jan;68(1):226-234. doi: 10.2337/db18-0857. Epub 2018 Nov 2.
• [9] ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma.Oncogene. 2019 Mar;38(12):2056-2075. doi: 10.1038/s41388-018-0543-2. Epub 2018 Nov 6.
• [10] Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages.Diabetes. 2018 Sep;67(9):1761-1772. doi: 10.2337/db17-1201. Epub 2018 Jun 26.
• [11] 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.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] MicroRNA 376c enhances ovarian cancer cell survival by targeting activin receptor-like kinase 7: implications for chemoresistance. J Cell Sci. 2011 Feb 1;124(Pt 3):359-68. doi: 10.1242/jcs.072223. Epub 2011 Jan 11.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.