Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2IDF27)

• DOT Name: Receptor for retinol uptake STRA6 (STRA6)
• Synonyms: Retinol-binding protein receptor STRA6; Stimulated by retinoic acid gene 6 protein homolog
• Gene Name: STRA6
• Related Disease:
  Gastric cancer
  Matthew-Wood syndrome
  Pulmonary disease
  Stomach cancer
  Type-1/2 diabetes
  Cardiac disease
  Coloboma
  Colonic neoplasm
  Myocardial infarction
  Neoplasm
  Osteoporosis
  Trichohepatoenteric syndrome
  Fetal growth restriction
  Intellectual disability
  Microphthalmia, isolated, with coloboma
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Disorder of orbital region
  Microphthalmia
  Rheumatoid arthritis
• UniProt ID: STRA6_HUMAN
• Pfam ID: PF14752
• Sequence:
  MSSQPAGNQTSPGATEDYSYGSWYIDEPQGGEELQPEGEVPSCHTSIPPGLYHACLASLS
  ILVLLLLAMLVRRRQLWPDCVRGRPGLPSPVDFLAGDRPRAVPAAVFMVLLSSLCLLLPD
  EDALPFLTLASAPSQDGKTEAPRGAWKILGLFYYAALYYPLAACATAGHTAAHLLGSTLS
  WAHLGVQVWQRAECPQVPKIYKYYSLLASLPLLLGLGFLSLWYPVQLVRSFSRRTGAGSK
  GLQSSYSEEYLRNLLCRKKLGSSYHTSKHGFLSWARVCLRHCIYTPQPGFHLPLKLVLSA
  TLTGTAIYQVALLLLVGVVPTIQKVRAGVTTDVSYLLAGFGIVLSEDKQEVVELVKHHLW
  ALEVCYISALVLSCLLTFLVLMRSLVTHRTNLRALHRGAALDLSPLHRSPHPSRQAIFCW
  MSFSAYQTAFICLGLLVQQIIFFLGTTALAFLVLMPVLHGRNLLLFRSLESSWPFWLTLA
  LAVILQNMAAHWVFLETHDGHPQLTNRRVLYAATFLLFPLNVLVGAMVATWRVLLSALYN
  AIHLGQMDLSLLPPRAATLDPGYYTYRNFLKIEVSQSHPAMTAFCSLLLQAQSLLPRTMA
  APQDSLRPGEEDEGMQLLQTKDSMAKGARPGASRGRARWGLAYTLLHNPTLQVFRKTALL
  GANGAQP
• Function: Functions as a retinol transporter. Accepts all-trans retinol from the extracellular retinol-binding protein RBP4, facilitates retinol transport across the cell membrane, and then transfers retinol to the cytoplasmic retinol-binding protein RBP1. Retinol uptake is enhanced by LRAT, an enzyme that converts retinol to all-trans retinyl esters, the storage forms of vitamin A. Contributes to the activation of a signaling cascade that depends on retinol transport and LRAT-dependent generation of retinol metabolites that then trigger activation of JAK2 and its target STAT5, and ultimately increase the expression of SOCS3 and inhibit cellular responses to insulin. Important for the homeostasis of vitamin A and its derivatives, such as retinoic acid. STRA6-mediated transport is particularly important in the eye, and under conditions of dietary vitamin A deficiency (Probable). Does not transport retinoic acid.
• Tissue Specificity: Broad expression. In adult eye expressed in sclera, retina, retinal pigment epithelium, and trabecular meshwork but not in choroid and iris.
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  Retinoid cycle disease events (R-HSA-2453864)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[1]
Matthew-Wood syndrome	DISA7HR7	Definitive	Autosomal recessive	[2]
Pulmonary disease	DIS6060I	Definitive	Biomarker	[3]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[4]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[5]
Coloboma	DISP39N5	Strong	Genetic Variation	[6]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Myocardial infarction	DIS655KI	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[9]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[10]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[5]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[10]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Colon cancer	DISVC52G	Limited	Biomarker	[11]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[11]
Disorder of orbital region	DISH0ECJ	Limited	Genetic Variation	[12]
Microphthalmia	DISGEBES	Limited	Genetic Variation	[13]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[14]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin A	DMJ2AH4	Approved	Receptor for retinol uptake STRA6 (STRA6) increases the transport of Vitamin A.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Receptor for retinol uptake STRA6 (STRA6).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[20]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Receptor for retinol uptake STRA6 (STRA6).	[21]
Permethrin	DMZ0Q1G	Approved	Permethrin affects the expression of Receptor for retinol uptake STRA6 (STRA6).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Receptor for retinol uptake STRA6 (STRA6).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Receptor for retinol uptake STRA6 (STRA6).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Receptor for retinol uptake STRA6 (STRA6).	[26]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Receptor for retinol uptake STRA6 (STRA6).	[22]

References

• [1] STRA6 exerts oncogenic role in gastric tumorigenesis by acting as a crucial target of miR-873.J Exp Clin Cancer Res. 2019 Nov 6;38(1):452. doi: 10.1186/s13046-019-1450-2.
• [2] First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype. Hum Mutat. 2011 Dec;32(12):1417-26. doi: 10.1002/humu.21590. Epub 2011 Sep 29.
• [3] Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet. 2007 Mar;80(3):550-60. doi: 10.1086/512203. Epub 2007 Jan 29.
• [4] O-GlcNAcylation disrupts STRA6-retinol signals in kidneys of diabetes.Biochim Biophys Acta Gen Subj. 2019 Jun;1863(6):1059-1069. doi: 10.1016/j.bbagen.2019.03.014. Epub 2019 Mar 21.
• [5] Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6. Am J Hum Genet. 2007 Jun;80(6):1179-87. doi: 10.1086/518177. Epub 2007 Apr 11.
• [6] The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. doi: 10.1016/j.ejmg.2014.05.002. Epub 2014 May 22.
• [7] Holo-retinol-binding protein and its receptor STRA6 drive oncogenic transformation.Cancer Res. 2014 Nov 1;74(21):6341-51. doi: 10.1158/0008-5472.CAN-14-1052. Epub 2014 Sep 18.
• [8] Early inhibition of endothelial retinoid uptake upon myocardial infarction restores cardiac function and prevents cell, tissue, and animal death.J Mol Cell Cardiol. 2019 Jan;126:105-117. doi: 10.1016/j.yjmcc.2018.11.012. Epub 2018 Nov 23.
• [9] STRA6 as a possible candidate gene for pathogenesis of osteoporosis from RNAseq analysis of human mesenchymal stem cells.Mol Med Rep. 2017 Oct;16(4):4075-4081. doi: 10.3892/mmr.2017.7072. Epub 2017 Jul 21.
• [10] Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia.Hum Mutat. 2009 May;30(5):E673-81. doi: 10.1002/humu.21023.
• [11] RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis.Stem Cell Reports. 2017 Aug 8;9(2):438-450. doi: 10.1016/j.stemcr.2017.06.002. Epub 2017 Jul 6.
• [12] ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm.Hum Mol Genet. 2013 Aug 15;22(16):3250-8. doi: 10.1093/hmg/ddt179. Epub 2013 Apr 15.
• [13] Mutation analysis of the STRA6 gene in isolated and non-isolated anophthalmia/microphthalmia.Clin Genet. 2013 Mar;83(3):244-50. doi: 10.1111/j.1399-0004.2012.01904.x. Epub 2012 Jul 4.
• [14] Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage.Cell Death Differ. 2013 Jul;20(7):910-9. doi: 10.1038/cdd.2013.14. Epub 2013 Mar 1.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome. Cell Metab. 2008 Mar;7(3):258-68. doi: 10.1016/j.cmet.2008.01.009.