Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT88HCDY)

• DOT Name: Ras-GEF domain-containing family member 1A (RASGEF1A)
• Gene Name: RASGEF1A
• Related Disease:
  B-cell lymphoma
  Hirschsprung disease
• UniProt ID: RGF1A_HUMAN
• Pfam ID: PF00617 ; PF00618
• Sequence:
  MPQTSVVFSSILGPSCSGQVQPGMGERGGGAGGGSGDLIFQDGHLISGSLEALMEHLVPT
  VDYYPDRTYIFTFLLSSRVFMPPHDLLARVGQICVEQKQQLEAGPEKAKLKSFSAKIVQL
  LKEWTEAFPYDFQDEKAMAELKAITHRVTQCDEENGTVKKAIAQMTQSLLLSLAARSQLQ
  ELREKLRPPAVDKGPILKTKPPAAQKDILGVCCDPLVLAQQLTHIELDRVSSIYPEDLMQ
  IVSHMDSLDNHRCRGDLTKTYSLEAYDNWFNCLSMLVATEVCRVVKKKHRTRMLEFFIDV
  ARECFNIGNFNSMMAIISGMNLSPVARLKKTWSKVKTAKFDVLEHHMDPSSNFCNYRTAL
  QGATQRSQMANSSREKIVIPVFNLFVKDIYFLHKIHTNHLPNGHINFKKFWEISRQIHEF
  MTWTQVECPFEKDKKIQSYLLTAPIYSEEALFVASFESEGPENHMEKDSWKTLRTTLLNR
  A
• Function: Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, KRAS, HRAS, and NRAS (in vitro). Plays a role in cell migration.
• Tissue Specificity: Detected in brain and spinal cord. Highly expressed in a number of intrahepatic cholangiocarcinoma tissue biopsies.
• Reactome Pathway: RAF/MAP kinase cascade (R-HSA-5673001)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[1]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[2]

5 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 Ras-GEF domain-containing family member 1A (RASGEF1A).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras-GEF domain-containing family member 1A (RASGEF1A).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ras-GEF domain-containing family member 1A (RASGEF1A).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras-GEF domain-containing family member 1A (RASGEF1A).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras-GEF domain-containing family member 1A (RASGEF1A).	[9]

2 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 increases the methylation of Ras-GEF domain-containing family member 1A (RASGEF1A).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Ras-GEF domain-containing family member 1A (RASGEF1A).	[8]

References

• [1] A Novel Non-Immunoglobulin (non-Ig)/BCL6 Translocation in Diffuse Large B-Cell Lymphoma Involving Chromosome 10q11.21 Loci and Review on Clinical Consequences of BCL6 Rearrangements.Pathol Oncol Res. 2016 Apr;22(2):233-43. doi: 10.1007/s12253-015-9972-1. Epub 2015 Aug 30.
• [2] A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease.PLoS One. 2014 Oct 13;9(10):e110292. doi: 10.1371/journal.pone.0110292. eCollection 2014.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.