Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX1BC5B)

• DOT Name: Protein lin-7 homolog B (LIN7B)
• Synonyms: Lin-7B; hLin7B; Mammalian lin-seven protein 2; MALS-2; Vertebrate lin-7 homolog 2; Veli-2; hVeli2
• Gene Name: LIN7B
• Related Disease:
  Autism spectrum disorder
  Huntington disease
  Pervasive developmental disorder
• UniProt ID: LIN7B_HUMAN
• PDB ID: 2DKR
• Pfam ID: PF02828 ; PF00595
• Sequence:
  MAALVEPLGLERDVSRAVELLERLQRSGELPPQKLQALQRVLQSRFCSAIREVYEQLYDT
  LDITGSAEIRAHATAKATVAAFTASEGHAHPRVVELPKTDEGLGFNIMGGKEQNSPIYIS
  RVIPGGVADRHGGLKRGDQLLSVNGVSVEGEQHEKAVELLKAAQGSVKLVVRYTPRVLEE
  MEARFEKMRSARRRQQHQSYSSLESRG
• Function: Plays a role in establishing and maintaining the asymmetric distribution of channels and receptors at the plasma membrane of polarized cells. Forms membrane-associated multiprotein complexes that may regulate delivery and recycling of proteins to the correct membrane domains. The tripartite complex composed of LIN7 (LIN7A, LIN7B or LIN7C), CASK and APBA1 associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules. This complex may have the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Ensures the proper localization of GRIN2B (subunit 2B of the NMDA receptor) to neuronal postsynaptic density and may function in localizing synaptic vesicles at synapses where it is recruited by beta-catenin and cadherin. Required to localize Kir2 channels, GABA transporter (SLC6A12) and EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 to the basolateral membrane of epithelial cells. May increase the amplitude of ASIC3 acid-evoked currents by stabilizing the channel at the cell surface.
• Reactome Pathway:
  RHO GTPases Activate Rhotekin and Rhophilins (R-HSA-5666185)
  Neurexins and neuroligins (R-HSA-6794361)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[1]

8 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 Protein lin-7 homolog B (LIN7B).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein lin-7 homolog B (LIN7B).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein lin-7 homolog B (LIN7B).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein lin-7 homolog B (LIN7B).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein lin-7 homolog B (LIN7B).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein lin-7 homolog B (LIN7B).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein lin-7 homolog B (LIN7B).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein lin-7 homolog B (LIN7B).	[10]

References

• [1] Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders.J Neurochem. 2015 Jan;132(1):61-9. doi: 10.1111/jnc.12943. Epub 2014 Sep 26.
• [2] Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease.J Neuropathol Exp Neurol. 2010 Sep;69(9):880-95. doi: 10.1097/NEN.0b013e3181ed7a41.
• [3] 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.
• [4] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.