Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WUWMU)

• DOT Name: Growth hormone receptor (GHR)
• Synonyms: GH receptor; Somatotropin receptor
• Gene Name: GHR
• Related Disease:
  Laron syndrome
  Short stature due to partial GHR deficiency
• UniProt ID: GHR_HUMAN
• PDB ID: 1A22; 1AXI; 1HWG; 1HWH; 1KF9; 2AEW; 3HHR; 5OEK; 5OHD
• Pfam ID: PF09067 ; PF00041 ; PF12772
• Sequence:
  MDLWQLLLTLALAGSSDAFSGSEATAAILSRAPWSLQSVNPGLKTNSSKEPKFTKCRSPE
  RETFSCHWTDEVHHGTKNLGPIQLFYTRRNTQEWTQEWKECPDYVSAGENSCYFNSSFTS
  IWIPYCIKLTSNGGTVDEKCFSVDEIVQPDPPIALNWTLLNVSLTGIHADIQVRWEAPRN
  ADIQKGWMVLEYELQYKEVNETKWKMMDPILTTSVPVYSLKVDKEYEVRVRSKQRNSGNY
  GEFSEVLYVTLPQMSQFTCEEDFYFPWLLIIIFGIFGLTVMLFVFLFSKQQRIKMLILPP
  VPVPKIKGIDPDLLKEGKLEEVNTILAIHDSYKPEFHSDDSWVEFIELDIDEPDEKTEES
  DTDRLLSSDHEKSHSNLGVKDGDSGRTSCCEPDILETDFNANDIHEGTSEVAQPQRLKGE
  ADLLCLDQKNQNNSPYHDACPATQQPSVIQAEKNKPQPLPTEGAESTHQAAHIQLSNPSS
  LSNIDFYAQVSDITPAGSVVLSPGQKNKAGMSQCDMHPEMVSLCQENFLMDNAYFCEADA
  KKCIPVAPHIKVESHIQPSLNQEDIYITTESLTTAAGRPGTGEHVPGSEMPVPDYTSIHI
  VQSPQGLILNATALPLPDKEFLSSCGYVSTDQLNKIMP
• Function: Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway; The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.; Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.
• Tissue Specificity: Expressed in various tissues with high expression in liver and skeletal muscle. Isoform 4 is predominantly expressed in kidney, bladder, adrenal gland and brain stem. Isoform 1 expression in placenta is predominant in chorion and decidua. Isoform 4 is highly expressed in placental villi. Isoform 2 is expressed in lung, stomach and muscle. Low levels in liver.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt sig.ling pathway (hsa04151)
  JAK-STAT sig.ling pathway (hsa04630)
  Growth hormone synthesis, secretion and action (hsa04935)
• Reactome Pathway:
  Growth hormone receptor signaling (R-HSA-982772)
  Prolactin receptor signaling (R-HSA-1170546)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Laron syndrome	DISW9H7W	Definitive	Autosomal recessive	[1]
Short stature due to partial GHR deficiency	DISU0GJP	Strong	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Growth hormone receptor (GHR).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Growth hormone receptor (GHR).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Growth hormone receptor (GHR).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Growth hormone receptor (GHR).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Growth hormone receptor (GHR).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Growth hormone receptor (GHR).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Growth hormone receptor (GHR).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Growth hormone receptor (GHR).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Growth hormone receptor (GHR).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Growth hormone receptor (GHR).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Growth hormone receptor (GHR).	[4]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Growth hormone receptor (GHR).	[13]

References

• [1] Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. 1998 Feb;83(2):531-7. doi: 10.1210/jcem.83.2.4601.
• [2] Functional characterization of truncated growth hormone (GH) receptor-(1-277) causing partial GH insensitivity syndrome with high GH-binding protein. J Clin Endocrinol Metab. 1999 Mar;84(3):1011-6. doi: 10.1210/jcem.84.3.5566.
• [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] 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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] 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.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] 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.