Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6GI23M)

• DOT Name: Ras-related protein Rab-11B (RAB11B)
• Synonyms: EC 3.6.5.2; GTP-binding protein YPT3
• Gene Name: RAB11B
• Related Disease:
  Neoplasm
  Adenocarcinoma
  Alzheimer disease
  HIV infectious disease
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Long QT syndrome 2
  Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter
  Pancreatic adenocarcinoma
  Bone osteosarcoma
  Neoplasm of esophagus
  Osteosarcoma
• UniProt ID: RB11B_HUMAN
• PDB ID: 2F9L; 2F9M; 4OJK
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MGTRDDEYDYLFKVVLIGDSGVGKSNLLSRFTRNEFNLESKSTIGVEFATRSIQVDGKTI
  KAQIWDTAGQERYRAITSAYYRGAVGALLVYDIAKHLTYENVERWLKELRDHADSNIVIM
  LVGNKSDLRHLRAVPTDEARAFAEKNNLSFIETSALDSTNVEEAFKNILTEIYRIVSQKQ
  IADRAAHDESPGNNVVDISVPPTTDGQKPNKLQCCQNL
• Function: The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. The small Rab GTPase RAB11B plays a role in endocytic recycling, regulating apical recycling of several transmembrane proteins including cystic fibrosis transmembrane conductance regulator/CFTR, epithelial sodium channel/ENaC, potassium voltage-gated channel, and voltage-dependent L-type calcium channel. May also regulate constitutive and regulated secretion, like insulin granule exocytosis. Required for melanosome transport and release from melanocytes. Also regulates V-ATPase intracellular transport in response to extracellular acidosis. Promotes Rabin8/RAB3IP preciliary vesicular trafficking to mother centriole by forming a ciliary targeting complex containing Rab11, ASAP1, Rabin8/RAB3IP, RAB11FIP3 and ARF4, thereby regulating ciliogenesis initiation (Probable). On the contrary, upon LPAR1 receptor signaling pathway activation, interaction with phosphorylated WDR44 prevents Rab11-RAB3IP-RAB11FIP3 complex formation and cilia growth (Probable).
• KEGG Pathway:
  Endocytosis (hsa04144)
  AMPK sig.ling pathway (hsa04152)
  Vasopressin-regulated water reabsorption (hsa04962)
  Influenza A (hsa05164)
• Reactome Pathway:
  RAB geranylgeranylation (R-HSA-8873719)
  TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
HIV infectious disease	DISO97HC	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[5]
Long QT syndrome 2	DISQQFTJ	Strong	Biomarker	[6]
Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter	DISUBWNH	Strong	Autosomal dominant	[5]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[8]
Neoplasm of esophagus	DISOLKAQ	Limited	Biomarker	[9]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[8]

1 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 Ras-related protein Rab-11B (RAB11B).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related protein Rab-11B (RAB11B).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-11B (RAB11B).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-11B (RAB11B).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ras-related protein Rab-11B (RAB11B).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ras-related protein Rab-11B (RAB11B).	[15]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Ras-related protein Rab-11B (RAB11B).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related protein Rab-11B (RAB11B).	[17]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Ras-related protein Rab-11B (RAB11B).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Ras-related protein Rab-11B (RAB11B).	[19]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Ras-related protein Rab-11B (RAB11B).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-11B (RAB11B).	[21]

References

• [1] Individual participant data pooled-analysis of risk factors for recurrence after neoadjuvant radiotherapy and transanal local excision of rectal cancer: the PARTTLE study.Tech Coloproctol. 2019 Sep;23(9):831-842. doi: 10.1007/s10151-019-02049-z. Epub 2019 Aug 6.
• [2] Prognostic significance of positive circumferential resection margin post neoadjuvant chemotherapy in patients with esophageal or gastro-esophageal junction adenocarcinoma.Eur J Surg Oncol. 2019 Mar;45(3):439-445. doi: 10.1016/j.ejso.2018.10.530. Epub 2018 Oct 24.
• [3] A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of -amyloid production.Cell Rep. 2013 Dec 26;5(6):1536-51. doi: 10.1016/j.celrep.2013.12.005.
• [4] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [5] Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype. Am J Hum Genet. 2017 Nov 2;101(5):824-832. doi: 10.1016/j.ajhg.2017.09.015. Epub 2017 Oct 26.
• [6] Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.Am J Physiol Cell Physiol. 2013 Nov 1;305(9):C919-30. doi: 10.1152/ajpcell.00406.2012. Epub 2013 Jul 17.
• [7] The 'TRIANGLE Operation' by Laparoscopy: Radical Pancreaticoduodenectomy with Major Vascular Resection for Borderline Resectable Pancreatic Head Cancer.Ann Surg Oncol. 2020 May;27(5):1613-1614. doi: 10.1245/s10434-019-08101-4. Epub 2019 Dec 4.
• [8] Long non-coding RNA RAB11B-AS1 prevents osteosarcoma development and progression via its natural antisense transcript RAB11B.Oncotarget. 2018 Jan 13;9(42):26770-26786. doi: 10.18632/oncotarget.24247. eCollection 2018 Jun 1.
• [9] Prognostic value of the circumferential resection margin and its definitions in esophageal cancer patients after neoadjuvant chemoradiotherapy.Dis Esophagus. 2018 Feb 1;31(2). doi: 10.1093/dote/dox117.
• [10] 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.
• [11] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. J Cell Biochem. 2008 Jun 1;104(3):1054-64. doi: 10.1002/jcb.21691.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Impact of epigallocatechin gallate on gene expression profiles of human hepatocellular carcinoma cell lines BEL7404/ADM and BEL7402/5-FU. Ai Zheng. 2008 Oct;27(10):1056-64.
• [19] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [20] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.