Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1WMVDH)

• DOT Name: PTB domain-containing engulfment adapter protein 1 (GULP1)
• Synonyms: Cell death protein 6 homolog; PTB domain adapter protein CED-6; Protein GULP
• Gene Name: GULP1
• Related Disease:
  Alzheimer disease
  Episodic kinesigenic dyskinesia 1
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Chronic obstructive pulmonary disease
  Niemann-Pick disease type B
  Pulmonary emphysema
  Adenocarcinoma
• UniProt ID: GULP1_HUMAN
• PDB ID: 6ITU
• Pfam ID: PF00640
• Sequence:
  MNRAFSRKKDKTWMHTPEALSKHFIPYNAKFLGSTEVEQPKGTEVVRDAVRKLKFARHIK
  KSEGQKIPKVELQISIYGVKILEPKTKEVQHNCQLHRISFCADDKTDKRIFTFICKDSES
  NKHLCYVFDSEKCAEEITLTIGQAFDLAYRKFLESGGKDVETRKQIAGLQKRIQDLETEN
  MELKNKVQDLENQLRITQVSAPPAGSMTPKSPSTDIFDMIPFSPISHQSSMPTRNGTQPP
  PVPSRSTEIKRDLFGAEPFDPFNCGAADFPPDIQSKLDEMQEGFKMGLTLEGTVFCLDPL
  DSRC
• Function: May function as an adapter protein. Required for efficient phagocytosis of apoptotic cells. Modulates cellular glycosphingolipid and cholesterol transport. May play a role in the internalization and endosomal trafficking of various LRP1 ligands, such as PSAP. Increases cellular levels of GTP-bound ARF6.
• Tissue Specificity: Widely expressed. Detected in macrophages, pancreas, kidney, skeletal muscle, heart, colon, intestine, lung, placenta and ovary.
• KEGG Pathway: Efferocytosis (hsa04148)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[3]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[3]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[3]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[4]
Niemann-Pick disease type B	DISVJCFK	moderate	Biomarker	[5]
Pulmonary emphysema	DIS5M7HZ	moderate	Altered Expression	[4]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	PTB domain-containing engulfment adapter protein 1 (GULP1) decreases the response to substance of Arsenic trioxide.	[27]

21 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 PTB domain-containing engulfment adapter protein 1 (GULP1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[19]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[20]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[21]
Methimazole	DM25FL8	Approved	Methimazole increases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[21]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of PTB domain-containing engulfment adapter protein 1 (GULP1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of PTB domain-containing engulfment adapter protein 1 (GULP1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of PTB domain-containing engulfment adapter protein 1 (GULP1).	[18]

References

• [1] GULP1/CED-6 ameliorates amyloid- toxicity in a Drosophila model of Alzheimer's disease.Oncotarget. 2017 Aug 8;8(59):99274-99283. doi: 10.18632/oncotarget.20062. eCollection 2017 Nov 21.
• [2] Attenuation of amyloid- generation by atypical protein kinase C-mediated phosphorylation of engulfment adaptor PTB domain containing 1 threonine 35.FASEB J. 2019 Nov;33(11):12019-12035. doi: 10.1096/fj.201802825RR. Epub 2019 Aug 5.
• [3] Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.Cancer Lett. 2018 Oct 1;433:242-251. doi: 10.1016/j.canlet.2018.06.030. Epub 2018 Jun 28.
• [4] Expression of GULP1 in bronchial epithelium is associated with the progression of emphysema in chronic obstructive pulmonary disease.Respir Med. 2017 Mar;124:72-78. doi: 10.1016/j.rmed.2017.02.011. Epub 2017 Feb 17.
• [5] Cholesterol trapping in Niemann-Pick disease type B fibroblasts can be relieved by expressing the phosphotyrosine binding domain of GULP.J Clin Lipidol. 2013 Mar-Apr;7(2):153-64. doi: 10.1016/j.jacl.2012.02.006. Epub 2012 Feb 22.
• [6] Engulfment protein GULP is regulator of transforming growth factor- response in ovarian cells.J Biol Chem. 2012 Jun 8;287(24):20636-51. doi: 10.1074/jbc.M111.314997. Epub 2012 Mar 26.
• [7] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways. BMC Cancer. 2005 Jul 7;5:74. doi: 10.1186/1471-2407-5-74.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] 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.
• [19] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [20] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [21] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [22] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] 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.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.