Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYC7M2A)

• DOT Name: Pleiotrophin (PTN)
• Synonyms: PTN; Heparin-binding brain mitogen; HBBM; Heparin-binding growth factor 8; HBGF-8; Heparin-binding growth-associated molecule; HB-GAM; Heparin-binding neurite outgrowth-promoting factor; HBNF; Heparin-binding neurite outgrowth-promoting factor 1; HBNF-1; Osteoblast-specific factor 1; OSF-1
• Gene Name: PTN
• UniProt ID: PTN_HUMAN
• PDB ID: 2N6F
• Pfam ID: PF01091 ; PF05196
• Sequence:
  MQAQQYQQQRRKFAAAFLAFIFILAAVDTAEAGKKEKPEKKVKKSDCGEWQWSVCVPTSG
  DCGLGTREGTRTGAECKQTMKTQRCKIPCNWKKQFGAECKYQFQAWGECDLNTALKTRTG
  SLKRALHNAECQKTVTISKPCGKLTKPKPQAESKKKKKEGKKQEKMLD
• Function: Secreted growth factor that mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors. Binds cell-surface proteoglycan receptor via their chondroitin sulfate (CS) groups. Thereby regulates many processes like cell proliferation, cell survival, cell growth, cell differentiation and cell migration in several tissues namely neuron and bone. Also plays a role in synaptic plasticity and learning-related behavior by inhibiting long-term synaptic potentiation. Binds PTPRZ1, leading to neutralization of the negative charges of the CS chains of PTPRZ1, inducing PTPRZ1 clustering, thereby causing the dimerization and inactivation of its phosphatase activity leading to increased tyrosine phosphorylation of each of the PTPRZ1 substrates like ALK, CTNNB1 or AFAP1L2 in order to activate the PI3K-AKT pathway. Through PTPRZ1 binding controls oligodendrocyte precursor cell differentiation by enhancing the phosphorylation of AFAP1L2 in order to activate the PI3K-AKT pathway. Forms a complex with PTPRZ1 and integrin alpha-V/beta-3 (ITGAV:ITGB3) that stimulates endothelial cell migration through SRC dephosphorylation and activation that consequently leads to ITGB3 'Tyr-773' phosphorylation. In adult hippocampus promotes dendritic arborization, spine development, and functional integration and connectivity of newborn granule neurons through ALK by activating AKT signaling pathway. Binds GPC2 and chondroitin sulfate proteoglycans (CSPGs) at the neuron surface, leading to abrogation of binding between PTPRS and CSPGs and neurite outgrowth promotion. Binds SDC3 and mediates bone formation by recruiting and attaching osteoblasts/osteoblast precursors to the sites for new bone deposition. Binds ALK and promotes cell survival and cell proliferation through MAPK pathway activation. Inhibits proliferation and enhances differentiation of neural stem cells by inhibiting FGF2-induced fibroblast growth factor receptor signaling pathway. Mediates regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. In addition may play a role in the female reproductive system, auditory response and the progesterone-induced decidualization pathway.
• Tissue Specificity: Osteoblast and brain.
• Reactome Pathway: Signaling by ALK (R-HSA-201556)

Molecular Interaction Atlas (MIA) of This DOT

14 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 Pleiotrophin (PTN).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pleiotrophin (PTN).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pleiotrophin (PTN).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleiotrophin (PTN).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Pleiotrophin (PTN).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Pleiotrophin (PTN).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Pleiotrophin (PTN).	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Pleiotrophin (PTN).	[8]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Pleiotrophin (PTN).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Pleiotrophin (PTN).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pleiotrophin (PTN).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pleiotrophin (PTN).	[15]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Pleiotrophin (PTN).	[16]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Pleiotrophin (PTN).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate affects the binding of Pleiotrophin (PTN).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pleiotrophin (PTN).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pleiotrophin (PTN).	[14]

References

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• [9] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [10] Specific molecular interactions of oversulfated chondroitin sulfate E with various heparin-binding growth factors. Implications as a physiological binding partner in the brain and other tissues. J Biol Chem. 2002 Nov 15;277(46):43707-16. doi: 10.1074/jbc.M207105200. Epub 2002 Sep 6.
• [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] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [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] 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.
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• [16] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [17] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.