Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8KT2AK)

• DOT Name: Dynein regulatory complex subunit 4 (GAS8)
• Synonyms: Growth arrest-specific protein 11; GAS-11; Growth arrest-specific protein 8; GAS-8
• Gene Name: GAS8
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Ciliopathy
  Colorectal carcinoma
  Multiple sclerosis
  Neoplasm
  Primary ciliary dyskinesia 1
  Primary ciliary dyskinesia 33
  Primary ciliary dyskinesia
  Hepatocellular carcinoma
• UniProt ID: DRC4_HUMAN
• PDB ID: 8J07
• Pfam ID: PF13851
• Sequence:
  MAPKKKGKKGKAKGTPIVDGLAPEDMSKEQVEEHVSRIREELDREREERNYFQLERDKIH
  TFWEITRRQLEEKKAELRNKDREMEEAEERHQVEIKVYKQKVKHLLYEHQNNLTEMKAEG
  TVVMKLAQKEHRIQESVLRKDMRALKVELKEQELASEVVVKNLRLKHTEEITRMRNDFER
  QVREIEAKYDKKMKMLRDELDLRRKTELHEVEERKNGQIHTLMQRHEEAFTDIKNYYNDI
  TLNNLALINSLKEQMEDMRKKEDHLEREMAEVSGQNKRLADPLQKAREEMSEMQKQLANY
  ERDKQILLCTKARLKVREKELKDLQWEHEVLEQRFTKVQQERDELYRKFTAAIQEVQQKT
  GFKNLVLERKLQALSAAVEKKEVQFNEVLAASNLDPAALTLVSRKLEDVLESKNSTIKDL
  QYELAQVCKAHNDLLRTYEAKLLAFGIPLDNVGFKPLETAVIGQTLGQGPAGLVGTPT
• Function: Component of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes. Plays an important role in the assembly of the N-DRC linker. Plays dual roles at both the primary (or non-motile) cilia to regulate hedgehog signaling and in motile cilia to coordinate cilia movement. Required for proper motile cilia functioning. Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity in a GRK2-dependent manner.
• Tissue Specificity: Expressed in respiratory epithelial cells (at protein level) . Expressed in the heart, skeletal muscle, pancreas, liver, brain, trachea and lung. Weakly or not expressed in placenta and kidney .
• Reactome Pathway: Activation of SMO (R-HSA-5635838)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Primary ciliary dyskinesia 1	DISPGX6H	Strong	GermlineCausalMutation	[7]
Primary ciliary dyskinesia 33	DISGOZX0	Strong	Autosomal recessive	[7]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[7]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Dynein regulatory complex subunit 4 (GAS8) increases the response to substance of Cisplatin.	[12]

2 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 Dynein regulatory complex subunit 4 (GAS8).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dynein regulatory complex subunit 4 (GAS8).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dynein regulatory complex subunit 4 (GAS8).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dynein regulatory complex subunit 4 (GAS8).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Dynein regulatory complex subunit 4 (GAS8).	[10]

References

• [1] Genomic profile of a Li-Fraumeni-like syndrome patient with a 45,X/46,XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome.Cancer Genet. 2015 Jun;208(6):341-4. doi: 10.1016/j.cancergen.2015.03.004. Epub 2015 Mar 19.
• [2] Characterization and screening for mutations of the growth arrest-specific 11 (GAS11) and C16orf3 genes at 16q24.3 in breast cancer.Genomics. 1998 Sep 15;52(3):325-31. doi: 10.1006/geno.1998.5457.
• [3] DRC2/CCDC65 is a central hub for assembly of the nexin-dynein regulatory complex and other regulators of ciliary and flagellar motility.Mol Biol Cell. 2018 Jan 15;29(2):137-153. doi: 10.1091/mbc.E17-08-0510. Epub 2017 Nov 22.
• [4] LncRNA GAS8-AS inhibits colorectal cancer (CRC) cell proliferation by downregulating lncRNA AFAP1-AS1.Gene. 2019 Aug 20;710:140-144. doi: 10.1016/j.gene.2019.05.040. Epub 2019 May 24.
• [5] GAS8 and its naturally occurring antisense RNA as biomarkers in multiple sclerosis.Immunobiology. 2019 Jul;224(4):560-564. doi: 10.1016/j.imbio.2019.04.005. Epub 2019 Apr 13.
• [6] The long noncoding RNA GAS8-AS1 suppresses hepatocarcinogenesis by epigenetically activating the tumor suppressor GAS8.J Biol Chem. 2018 Nov 2;293(44):17154-17165. doi: 10.1074/jbc.RA118.003055. Epub 2018 Sep 18.
• [7] Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex. Am J Hum Genet. 2015 Oct 1;97(4):546-54. doi: 10.1016/j.ajhg.2015.08.012. Epub 2015 Sep 17.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 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.
• [11] 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.
• [12] Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans. PLoS One. 2011;6(7):e21920. doi: 10.1371/journal.pone.0021920. Epub 2011 Jul 6.