Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG7EDZL)

• DOT Name: Transforming growth factor beta activator LRRC32 (LRRC32)
• Synonyms: Garpin; Glycoprotein A repetitions predominant; GARP; Leucine-rich repeat-containing protein 32
• Gene Name: LRRC32
• Related Disease: Cleft palate, proliferative retinopathy, and developmental delay
• UniProt ID: LRC32_HUMAN
• PDB ID: 6GFF; 8C7H
• Pfam ID: PF13855 ; PF01462
• Sequence:
  MRPQILLLLALLTLGLAAQHQDKVPCKMVDKKVSCQVLGLLQVPSVLPPDTETLDLSGNQ
  LRSILASPLGFYTALRHLDLSTNEISFLQPGAFQALTHLEHLSLAHNRLAMATALSAGGL
  GPLPRVTSLDLSGNSLYSGLLERLLGEAPSLHTLSLAENSLTRLTRHTFRDMPALEQLDL
  HSNVLMDIEDGAFEGLPRLTHLNLSRNSLTCISDFSLQQLRVLDLSCNSIEAFQTASQPQ
  AEFQLTWLDLRENKLLHFPDLAALPRLIYLNLSNNLIRLPTGPPQDSKGIHAPSEGWSAL
  PLSAPSGNASGRPLSQLLNLDLSYNEIELIPDSFLEHLTSLCFLNLSRNCLRTFEARRLG
  SLPCLMLLDLSHNALETLELGARALGSLRTLLLQGNALRDLPPYTFANLASLQRLNLQGN
  RVSPCGGPDEPGPSGCVAFSGITSLRSLSLVDNEIELLRAGAFLHTPLTELDLSSNPGLE
  VATGALGGLEASLEVLALQGNGLMVLQVDLPCFICLKRLNLAENRLSHLPAWTQAVSLEV
  LDLRNNSFSLLPGSAMGGLETSLRRLYLQGNPLSCCGNGWLAAQLHQGRVDVDATQDLIC
  RFSSQEEVSLSHVRPEDCEKGGLKNINLIIILTFILVSAILLTTLAACCCVRRQKFNQQY
  KA
• Function: Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta. Able to outcompete LTBP1 for binding to LAP regulatory chain of TGF-beta. Controls activation of TGF-beta-1 (TGFB1) on the surface of activated regulatory T-cells (Tregs). Required for epithelial fusion during palate development by regulating activation of TGF-beta-3 (TGFB3).
• Tissue Specificity: Preferentially expressed in regulatory T-cells (Tregs).
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cleft palate, proliferative retinopathy, and developmental delay	DIS8TX4M	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Transforming growth factor beta activator LRRC32 (LRRC32).	[11]

References

• [1] Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) 3 and is essential for mouse palatogenesis. J Biol Chem. 2017 Nov 3;292(44):18091-18097. doi: 10.1074/jbc.M117.797613. Epub 2017 Sep 14.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [6] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [9] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [10] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.