Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRH1E2T)

• DOT Name: Ras-related protein Rab-35 (RAB35)
• Synonyms: GTP-binding protein RAY; Ras-related protein Rab-1C
• Gene Name: RAB35
• Related Disease:
  Advanced cancer
  Hepatocellular carcinoma
  Mantle cell lymphoma
  Neoplasm
  Parkinson disease
  Progressive supranuclear palsy
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Stomach cancer
• UniProt ID: RAB35_HUMAN
• PDB ID: 3TW8; 6EKK; 6IF2; 6IF3
• Pfam ID: PF00071
• Sequence:
  MARDYDHLFKLLIIGDSGVGKSSLLLRFADNTFSGSYITTIGVDFKIRTVEINGEKVKLQ
  IWDTAGQERFRTITSTYYRGTHGVIVVYDVTSAESFVNVKRWLHEINQNCDDVCRILVGN
  KNDDPERKVVETEDAYKFAGQMGIQLFETSAKENVNVEEMFNCITELVLRAKKDNLAKQQ
  QQQQNDVVKLTKNSKRKKRCC
• 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 sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in the process of endocytosis and is an essential rate-limiting regulator of the fast recycling pathway back to the plasma membrane. During cytokinesis, required for the postfurrowing terminal steps, namely for intercellular bridge stability and abscission, possibly by controlling phosphatidylinositol 4,5-bis phosphate (PIP2) and SEPT2 localization at the intercellular bridge. May indirectly regulate neurite outgrowth. Together with TBC1D13 may be involved in regulation of insulin-induced glucose transporter SLC2A4/GLUT4 translocation to the plasma membrane in adipocytes.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Parkinson disease	DISQVHKL	Strong	Biomarker	[4]
Progressive supranuclear palsy	DISO5KRQ	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[5]
Lung cancer	DISCM4YA	Limited	Altered Expression	[6]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[6]
Stomach cancer	DISKIJSX	Limited	Biomarker	[5]

11 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-related protein Rab-35 (RAB35).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Ras-related protein Rab-35 (RAB35).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rab-35 (RAB35).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-35 (RAB35).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-35 (RAB35).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-35 (RAB35).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras-related protein Rab-35 (RAB35).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related protein Rab-35 (RAB35).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Ras-related protein Rab-35 (RAB35).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related protein Rab-35 (RAB35).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-35 (RAB35).	[16]

References

• [1] Rab35-dependent extracellular nanovesicles are required for induction of tumour supporting stroma.Nanoscale. 2018 May 10;10(18):8547-8559. doi: 10.1039/c8nr02417k.
• [2] Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma.Mol Cancer. 2019 Apr 3;18(1):78. doi: 10.1186/s12943-019-0990-6.
• [3] Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus.Leuk Lymphoma. 2017 Dec;58(12):2824-2832. doi: 10.1080/10428194.2017.1326034. Epub 2017 May 30.
• [4] Combined Assessment of Serum Alpha-Synuclein and Rab35 is a Better Biomarker for Parkinson's Disease.J Clin Neurol. 2019 Oct;15(4):488-495. doi: 10.3988/jcn.2019.15.4.488.
• [5] EGF Stimulates Rab35 Activation and Gastric Cancer Cell Migration by Regulating DENND1A-Grb2 Complex Formation.Front Pharmacol. 2018 Nov 22;9:1343. doi: 10.3389/fphar.2018.01343. eCollection 2018.
• [6] EGF-stimulated activation of Rab35 regulates RUSC2-GIT2 complex formation to stabilize GIT2 during directional lung cancer cell migration.Cancer Lett. 2016 Aug 28;379(1):70-83. doi: 10.1016/j.canlet.2016.05.027. Epub 2016 May 26.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] 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.