Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAIAS93)

• DOT Name: Rabenosyn-5 (RBSN)
• Synonyms: 110 kDa protein; FYVE finger-containing Rab5 effector protein rabenosyn-5; RAB effector RBSN; Zinc finger FYVE domain-containing protein 20
• Gene Name: RBSN
• Related Disease:
  Colorectal neoplasm
  Congenital neutropenia-myelofibrosis-nephromegaly syndrome
• UniProt ID: RBNS5_HUMAN
• PDB ID: 1YZM; 1Z0J; 1Z0K
• Pfam ID: PF01363 ; PF16601 ; PF11464
• Sequence:
  MASLDDPGEVREGFLCPLCLKDLQSFYQLHSHYEEEHSGEDRDVKGQIKSLVQKAKKAKD
  RLLKREGDDRAESGTQGYESFSYGGVDPYMWEPQELGAVRSHLSDFKKHRAARIDHYVVE
  VNKLIIRLEKLTAFDRTNTESAKIRAIEKSVVPWVNDQDVPFCPDCGNKFSIRNRRHHCR
  LCGSIMCKKCMELISLPLANKLTSASKESLSTHTSPSQSPNSVHGSRRGSISSMSSVSSV
  LDEKDDDRIRCCTHCKDTLLKREQQIDEKEHTPDIVKLYEKLRLCMEKVDQKAPEYIRMA
  ASLNAGETTYSLEHASDLRVEVQKVYELIDALSKKILTLGLNQDPPPHPSNLRLQRMIRY
  SATLFVQEKLLGLMSLPTKEQFEELKKKRKEEMERKRAVERQAALESQRRLEERQSGLAS
  RAANGEVASLRRGPAPLRKAEGWLPLSGGQGQSEDSDPLLQQIHNITSFIRQAKAAGRMD
  EVRTLQENLRQLQDEYDQQQTEKAIELSRRQAEEEDLQREQLQMLRERELEREREQFRVA
  SLHTRTRSLDFREIGPFQLEPSREPRTHLAYALDLGSSPVPSSTAPKTPSLSSTQPTRVW
  SGPPAVGQERLPQSSMPQQHEGPSLNPFDEEDLSSPMEEATTGPPAAGVSLDPSARILKE
  YNPFEEEDEEEEAVAGNPFIQPDSPAPNPFSEEDEHPQQRLSSPLVPGNPFEEPTCINPF
  EMDSDSGPEAEEPIEEELLLQQIDNIKAYIFDAKQCGRLDEVEVLTENLRELKHTLAKQK
  GGTD
• Function: Rab4/Rab5 effector protein acting in early endocytic membrane fusion and membrane trafficking of recycling endosomes. Required for endosome fusion either homotypically or with clathrin coated vesicles. Plays a role in the lysosomal trafficking of CTSD/cathepsin D from the Golgi to lysosomes. Also promotes the recycling of transferrin directly from early endosomes to the plasma membrane. Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate (PtdInsP3). Plays a role in the recycling of transferrin receptor to the plasma membrane.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Toll Like Receptor 9 (TLR9) Cascade (R-HSA-168138)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[1]
Congenital neutropenia-myelofibrosis-nephromegaly syndrome	DIS8VOO2	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Rabenosyn-5 (RBSN).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rabenosyn-5 (RBSN).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rabenosyn-5 (RBSN).	[7]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Rabenosyn-5 (RBSN).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rabenosyn-5 (RBSN).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rabenosyn-5 (RBSN).	[5]

References

• [1] Rad51C-ATXN7 fusion gene expression in colorectal tumors.Mol Cancer. 2016 Jun 13;15(1):47. doi: 10.1186/s12943-016-0527-1.
• [2] Syndromic congenital myelofibrosis associated with a loss-of-function variant in RBSN. Blood. 2018 Aug 9;132(6):658-662. doi: 10.1182/blood-2017-12-824433. Epub 2018 May 21.
• [3] 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.
• [4] 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.
• [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] 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.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.