Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMB4IXD)

• DOT Name: Dynactin subunit 2 (DCTN2)
• Synonyms: 50 kDa dynein-associated polypeptide; Dynactin complex 50 kDa subunit; DCTN-50; p50 dynamitin
• Gene Name: DCTN2
• Related Disease:
  Bone osteosarcoma
  Charcot marie tooth disease
  Osteosarcoma
  Cutaneous melanoma
  Melanoma
• UniProt ID: DCTN2_HUMAN
• Pfam ID: PF04912
• Sequence:
  MADPKYADLPGIARNEPDVYETSDLPEDDQAEFDAEELTSTSVEHIIVNPNAAYDKFKDK
  RVGTKGLDFSDRIGKTKRTGYESGEYEMLGEGLGVKETPQQKYQRLLHEVQELTTEVEKI
  KTTVKESATEEKLTPVLLAKQLAALKQQLVASHLEKLLGPDAAINLTDPDGALAKRLLLQ
  LEATKNSKGGSGGKTTGTPPDSSLVTYELHSRPEQDKFSQAAKVAELEKRLTELETAVRC
  DQDAQNPLSAGLQGACLMETVELLQAKVSALDLAVLDQVEARLQSVLGKVNEIAKHKASV
  EDADTQSKVHQLYETIQRWSPIASTLPELVQRLVTIKQLHEQAMQFGQLLTHLDTTQQMI
  ANSLKDNTTLLTQVQTTMRENLATVEGNFASIDERMKKLGK
• Function: Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules. In the dynactin soulder domain, binds the ACTR1A filament and acts as a molecular ruler to determine the length. Modulates cytoplasmic dynein binding to an organelle, and plays a role in prometaphase chromosome alignment and spindle organization during mitosis. Involved in anchoring microtubules to centrosomes. May play a role in synapse formation during brain development.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Vasopressin-regulated water reabsorption (hsa04962)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand (R-HSA-3371497)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  AURKA Activation by TPX2 (R-HSA-8854518)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[1]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[2]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[1]
Cutaneous melanoma	DIS3MMH9	Limited	Biomarker	[3]
Melanoma	DIS1RRCY	Limited	Biomarker	[3]

7 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 Dynactin subunit 2 (DCTN2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dynactin subunit 2 (DCTN2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dynactin subunit 2 (DCTN2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynactin subunit 2 (DCTN2).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Dynactin subunit 2 (DCTN2).	[8]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Dynactin subunit 2 (DCTN2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dynactin subunit 2 (DCTN2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dynactin subunit 2 (DCTN2).	[10]

References

• [1] Phenotypic changes associated with DYNACTIN-2 (DCTN2) over expression characterise SJSA-1 osteosarcoma cells.Mol Carcinog. 2006 Mar;45(3):157-63. doi: 10.1002/mc.20151.
• [2] Variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A are associated with intermediate Charcot-Marie-Tooth disease in a Norwegian family.Acta Neurol Scand. 2016 Jul;134(1):67-75. doi: 10.1111/ane.12515. Epub 2015 Oct 12.
• [3] Prognostic Value of Dynactin mRNA Expression in Cutaneous Melanoma.Med Sci Monit. 2018 Jun 4;24:3752-3763. doi: 10.12659/MSM.910566.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] 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.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [10] 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.
• [11] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.