Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH3WGLG)

• DOT Name: Ras-related protein Rab-21 (RAB21)
• Gene Name: RAB21
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Colorectal carcinoma
  Glioma
  Obesity
  Breast cancer
  Breast carcinoma
• UniProt ID: RAB21_HUMAN
• PDB ID: 1YZT; 1YZU; 1Z08; 1Z0I; 2OT3
• Pfam ID: PF00071
• Sequence:
  MAAAGGGGGGAAAAGRAYSFKVVLLGEGCVGKTSLVLRYCENKFNDKHITTLQASFLTKK
  LNIGGKRVNLAIWDTAGQERFHALGPIYYRDSNGAILVYDITDEDSFQKVKNWVKELRKM
  LGNEICLCIVGNKIDLEKERHVSIQEAESYAESVGAKHYHTSAKQNKGIEELFLDLCKRM
  IETAQVDERAKGNGSSQPGTARRGVQIIDDEPQAQTSGGGCCSSG
• Function: Small GTPase involved in membrane trafficking control. During the mitosis of adherent cells, controls the endosomal trafficking of integrins which is required for the successful completion of cytokinesis. Regulates integrin internalization and recycling, but does not influence the traffic of endosomally translocated receptors in general. As a result, may regulate cell adhesion and migration. Involved in neurite growth. Following SBF2/MTMT13-mediated activation in response to starvation-induced autophagy, binds to and regulates SNARE protein VAMP8 endolysosomal transport required for SNARE-mediated autophagosome-lysosome fusion. Modulates protein levels of the cargo receptors TMED2 and TMED10, and required for appropriate Golgi localization of TMED10.
• Tissue Specificity: Widely expressed. In jejunal tissue, predominantly expressed in the apical region of the epithelial cell layer of the villi, weak expression, if any, in the crypt epithelium. Capillary endothelium and some cell types in the lamina propria also show expression.
• Reactome Pathway:
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  RAB geranylgeranylation (R-HSA-8873719)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras-related protein Rab-21 (RAB21).	[7]

11 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 Ras-related protein Rab-21 (RAB21).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Ras-related protein Rab-21 (RAB21).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-21 (RAB21).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-21 (RAB21).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ras-related protein Rab-21 (RAB21).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ras-related protein Rab-21 (RAB21).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Ras-related protein Rab-21 (RAB21).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras-related protein Rab-21 (RAB21).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-21 (RAB21).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras-related protein Rab-21 (RAB21).	[14]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Ras-related protein Rab-21 (RAB21).	[16]

References

• [1] Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo.Oncogene. 2012 Aug 2;31(31):3597-606. doi: 10.1038/onc.2011.527. Epub 2011 Nov 28.
• [2] Rab21, a Novel PS1 Interactor, Regulates -Secretase Activity via PS1 Subcellular Distribution.Mol Neurobiol. 2018 May;55(5):3841-3855. doi: 10.1007/s12035-017-0606-3. Epub 2017 May 25.
• [3] Colorectal cancer cells respond differentially to autophagy inhibition in vivo.Sci Rep. 2019 Aug 5;9(1):11316. doi: 10.1038/s41598-019-47659-7.
• [4] Knockdown of Rab21 inhibits proliferation and induces apoptosis in human glioma cells.Cell Mol Biol Lett. 2017 Dec 19;22:30. doi: 10.1186/s11658-017-0062-0. eCollection 2017.
• [5] Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.Nat Genet. 2018 Jan;50(1):26-41. doi: 10.1038/s41588-017-0011-x. Epub 2017 Dec 22.
• [6] MiR-183/-96/-182 cluster is up-regulated in most breast cancers and increases cell proliferation and migration.Breast Cancer Res. 2014 Nov 14;16(6):473. doi: 10.1186/s13058-014-0473-z.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.