Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB07MOG)

• DOT Name: Shootin-1 (SHTN1)
• Synonyms: Shootin1
• Gene Name: SHTN1
• Related Disease:
  Cleft lip/palate
  Isolated cleft lip
  Non-small-cell lung cancer
• UniProt ID: SHOT1_HUMAN
• Sequence:
  MNSSDEEKQLQLITSLKEQAIGEYEDLRAENQKTKEKCDKIRQERDEAVKKLEEFQKISH
  MVIEEVNFMQNHLEIEKTCRESAEALATKLNKENKTLKRISMLYMAKLGPDVITEEINID
  DEDSTTDTDGAAETCVSVQCQKQIKELRDQIVSVQEEKKILAIELENLKSKLVEVIEEVN
  KVKQEKTVLNSEVLEQRKVLEKCNRVSMLAVEEYEEMQVNLELEKDLRKKAESFAQEMFI
  EQNKLKRQSHLLLQSSIPDQQLLKALDENAKLTQQLEEERIQHQQKVKELEEQLENETLH
  KEIHNLKQQLELLEEDKKELELKYQNSEEKARNLKHSVDELQKRVNQSENSVPPPPPPPP
  PLPPPPPNPIRSLMSMIRKRSHPSGSGAKKEKATQPETTEEVTDLKRQAVEEMMDRIKKG
  VHLRPVNQTARPKTKPESSKGCESAVDELKGILGTLNKSTSSRSLKSLDPENSETELERI
  LRRRKVTAEADSSSPTGILATSESKSMPVLGSVSSVTKTALNKKTLEAEFNSPSPPTPEP
  GEGPRKLEGCTSSKVTFQPPSSIGCRKKYIDGEKQAEPVVVLDPVSTHEPQTKDQVAEKD
  PTQHKEDEGEIQPENKEDSIENVRETDSSNC
• Function: Involved in the generation of internal asymmetric signals required for neuronal polarization and neurite outgrowth. Mediates netrin-1-induced F-actin-substrate coupling or 'clutch engagement' within the axon growth cone through activation of CDC42, RAC1 and PAK1-dependent signaling pathway, thereby converting the F-actin retrograde flow into traction forces, concomitantly with filopodium extension and axon outgrowth. Plays a role in cytoskeletal organization by regulating the subcellular localization of phosphoinositide 3-kinase (PI3K) activity at the axonal growth cone. Also plays a role in regenerative neurite outgrowth. In the developing cortex, cooperates with KIF20B to promote both the transition from the multipolar to the bipolar stage and the radial migration of cortical neurons from the ventricular zone toward the superficial layer of the neocortex. Involved in the accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the growth cone of primary hippocampal neurons.
• Reactome Pathway: Recycling pathway of L1 (R-HSA-437239)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[1]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Shootin-1 (SHTN1) affects the response to substance of Vinblastine.	[16]

12 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 Shootin-1 (SHTN1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Shootin-1 (SHTN1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Shootin-1 (SHTN1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Shootin-1 (SHTN1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Shootin-1 (SHTN1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Shootin-1 (SHTN1).	[9]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Shootin-1 (SHTN1).	[10]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Shootin-1 (SHTN1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Shootin-1 (SHTN1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Shootin-1 (SHTN1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Shootin-1 (SHTN1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Shootin-1 (SHTN1).	[15]

2 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 Shootin-1 (SHTN1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Shootin-1 (SHTN1).	[14]

References

• [1] A Population-Based Study of Effects of Genetic Loci on Orofacial Clefts.J Dent Res. 2017 Oct;96(11):1322-1329. doi: 10.1177/0022034517716914. Epub 2017 Jun 29.
• [2] Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology.PLoS Genet. 2018 Aug 1;14(8):e1007501. doi: 10.1371/journal.pgen.1007501. eCollection 2018 Aug.
• [3] Detection of Known and Novel FGFR Fusions in Non-Small Cell Lung Cancer by Comprehensive Genomic Profiling.J Thorac Oncol. 2019 Jan;14(1):54-62. doi: 10.1016/j.jtho.2018.09.014. Epub 2018 Sep 26.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] 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.
• [14] 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.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.