Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEYO9TM)

• DOT Name: Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2)
• Synonyms: AGAP-2; Centaurin-gamma-1; Cnt-g1; GTP-binding and GTPase-activating protein 2; GGAP2; Phosphatidylinositol 3-kinase enhancer; PIKE
• Gene Name: AGAP2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Glioblastoma multiforme
  Glioma
  Multiple sclerosis
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Prostate neoplasm
  Schwannoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: AGAP2_HUMAN
• PDB ID: 2BMJ; 2IWR; 2RLO
• Pfam ID: PF12796 ; PF01412 ; PF00071
• Sequence:
  MSRGAGALQRRTTTYLISLTLVKLESVPPPPPSPSAAAVGAPGARGSEPRDPGSPRGAEE
  PGKKRHERLFHRQDALWISTSSAGAGGAEPPALSPAPASPARPVSPAPGRRLSLWAAPPG
  PPLSGGLSPDSKPGGAPSSSRRPLLSSPSWGGPEPEGRTGGGVPGSSSPHPGTGSRRLKV
  APPPPAPKPCKTVTTSGAKAGGGKGAGSRLSWPESEGKPRVKGSKSSAGTGASVSAAATA
  AAAGGGGSTASTSGGVGAGAGARGKLSPRKGKSKTLDNSDLHPGPPAGSPPPLTLPPTPS
  PATAVTAASAQPPGPAPPITLEPPAPGLKRGREGGRASTRDRKMLKFISGIFTKSTGGPP
  GSGPLPGPPSLSSGSGSRELLGAELRASPKAVINSQEWTLSRSIPELRLGVLGDARSGKS
  SLIHRFLTGSYQVLEKTESEQYKKEMLVDGQTHLVLIREEAGAPDAKFSGWADAVIFVFS
  LEDENSFQAVSRLHGQLSSLRGEGRGGLALALVGTQDRISASSPRVVGDARARALCADMK
  RCSYYETCATYGLNVDRVFQEVAQKVVTLRKQQQLLAACKSLPSSPSHSAASTPVAGQAS
  NGGHTSDYSSSLPSSPNVGHRELRAEAAAVAGLSTPGSLHRAAKRRTSLFANRRGSDSEK
  RSLDSRGETTGSGRAIPIKQSFLLKRSGNSLNKEWKKKYVTLSSNGFLLYHPSINDYIHS
  THGKEMDLLRTTVKVPGKRPPRAISAFGPSASINGLVKDMSTVQMGEGLEATTPMPSPSP
  SPSSLQPPPDQTSKHLLKPDRNLARALSTDCTPSGDLSPLSREPPPSPMVKKQRRKKLTT
  PSKTEGSAGQAEAKRKMWKLKSFGSLRNIYKAEENFEFLIVSSTGQTWHFEAASFEERDA
  WVQAIESQILASLQCCESSKVKLRTDSQSEAVAIQAIRNAKGNSICVDCGAPNPTWASLN
  LGALICIECSGIHRNLGTHLSRVRSLDLDDWPRELTLVLTAIGNDTANRVWESDTRGRAK
  PSRDSSREERESWIRAKYEQLLFLAPLSTSEEPLGRQLWAAVQAQDVATVLLLLAHARHG
  PLDTSVEDPQLRSPLHLAAELAHVVITQLLLWYGADVAARDAQGRTALFYARQAGSQLCA
  DILLQHGCPGEGGSAATTPSAATTPSITATPSPRRRSSAASVGRADAPVALV
• Function: GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion.
• Tissue Specificity: Isoform 1 is brain-specific. Isoform 2 is ubiquitously expressed, with highest levels in brain and heart.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Endocytosis (hsa04144)
• Reactome Pathway: Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[7]
Obesity	DIS47Y1K	Strong	Altered Expression	[8]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[9]
Schwannoma	DISTTVLA	moderate	Genetic Variation	[10]
Prostate cancer	DISF190Y	Limited	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2).	[12]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 (AGAP2).	[16]

References

• [1] Co-amplification of phosphoinositide 3-kinase enhancer A and cyclin-dependent kinase 4 triggers glioblastoma progression.Oncogene. 2017 Aug 10;36(32):4562-4572. doi: 10.1038/onc.2017.67. Epub 2017 Apr 3.
• [2] Cellular energy stress induces AMPK-mediated regulation of glioblastoma cell proliferation by PIKE-A phosphorylation.Cell Death Dis. 2019 Mar 4;10(3):222. doi: 10.1038/s41419-019-1452-1.
• [3] Promoter DNA hypermethylation - Implications for Alzheimer's disease.Neurosci Lett. 2019 Oct 15;711:134403. doi: 10.1016/j.neulet.2019.134403. Epub 2019 Jul 24.
• [4] Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2.Aging (Albany NY). 2019 Aug 5;11(15):5300-5318. doi: 10.18632/aging.102092. Epub 2019 Aug 5.
• [5] Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.Nature. 2011 Aug 10;476(7359):214-9. doi: 10.1038/nature10251.
• [6] Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity.Cell Death Differ. 2016 Jan;23(1):52-63. doi: 10.1038/cdd.2015.66. Epub 2015 May 22.
• [7] Prognostic and diagnostic significance of long non-coding RNA AGAP2-AS1 levels in patients with non-small cell lung cancer.Eur Rev Med Pharmacol Sci. 2017 May;21(10):2392-2396.
• [8] Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet.PLoS One. 2017 Feb 7;12(2):e0171664. doi: 10.1371/journal.pone.0171664. eCollection 2017.
• [9] GGAP2/PIKE-a directly activates both the Akt and nuclear factor-kappaB pathways and promotes prostate cancer progression.Cancer Res. 2009 Feb 1;69(3):819-27. doi: 10.1158/0008-5472.CAN-08-2537. Epub 2009 Jan 27.
• [10] Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L.Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18200-5. doi: 10.1073/pnas.0405971102. Epub 2004 Dec 14.
• [11] SP1 and RAR regulate AGAP2 expression in cancer.Sci Rep. 2019 Jan 23;9(1):390. doi: 10.1038/s41598-018-36888-x.
• [12] 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.
• [13] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.