Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOE443G)

DOT Name	Endophilin-A1 (SH3GL2)
Synonyms	EEN-B1; Endophilin-1; SH3 domain protein 2A; SH3 domain-containing GRB2-like protein 2
Gene Name	SH3GL2
Related Disease	Adult glioblastoma ( ) Multiple sclerosis ( ) Alzheimer disease ( ) Amyloidosis ( ) Breast cancer ( ) Breast neoplasm ( ) Epilepsy ( ) Glioma ( ) Head-neck squamous cell carcinoma ( ) Human papillomavirus infection ( ) Laryngeal carcinoma ( ) Laryngeal squamous cell carcinoma ( ) Metastatic malignant neoplasm ( ) Non-small-cell lung cancer ( ) Schizophrenia ( ) Temporal lobe epilepsy ( ) Transitional cell carcinoma ( ) Urothelial carcinoma ( ) Breast carcinoma ( ) Clear cell renal carcinoma ( ) Glioblastoma multiforme ( ) Renal cell carcinoma ( ) Parkinson disease ( )
UniProt ID	SH3G2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1X03; 1X04; 2D4C; 2DBM
Pfam ID	PF03114 ; PF07653
Sequence	MSVAGLKKQFHKATQKVSEKVGGAEGTKLDDDFKEMERKVDVTSRAVMEIMTKTIEYLQP NPASRAKLSMINTMSKIRGQEKGPGYPQAEALLAEAMLKFGRELGDDCNFGPALGEVGEA MRELSEVKDSLDIEVKQNFIDPLQNLHDKDLREIQHHLKKLEGRRLDFDYKKKRQGKIPD EELRQALEKFDESKEIAESSMFNLLEMDIEQVSQLSALVQAQLEYHKQAVQILQQVTVRL EERIRQASSQPRREYQPKPRMSLEFPTGDSTQPNGGLSHTGTPKPSGVQMDQPCCRALYD FEPENEGELGFKEGDIITLTNQIDENWYEGMLHGHSGFFPINYVEILVALPH
Function	Implicated in synaptic vesicle endocytosis. May recruit other proteins to membranes with high curvature. Required for BDNF-dependent dendrite outgrowth. Cooperates with SH3GL2 to mediate BDNF-NTRK2 early endocytic trafficking and signaling from early endosomes.
Tissue Specificity	Brain, mostly in frontal cortex. Expressed at high level in fetal cerebellum.
KEGG Pathway	Endocytosis (hsa04144 )
Reactome Pathway	EGFR downregulation (R-HSA-182971 ) MHC class II antigen presentation (R-HSA-2132295 ) Lysosome Vesicle Biogenesis (R-HSA-432720 ) Golgi Associated Vesicle Biogenesis (R-HSA-432722 ) Recycling pathway of L1 (R-HSA-437239 ) Negative regulation of MET activity (R-HSA-6807004 ) Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825 ) Clathrin-mediated endocytosis (R-HSA-8856828 ) InlB-mediated entry of Listeria monocytogenes into host cell (R-HSA-8875360 ) Retrograde neurotrophin signalling (R-HSA-177504 )

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[6]
Epilepsy	DISBB28L	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[8]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[9]
Laryngeal carcinoma	DISNHCIV	Strong	Altered Expression	[10]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[13]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[7]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[14]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[14]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[5]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[15]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[1]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[15]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[16]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Endophilin-A1 (SH3GL2).	[17]
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6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endophilin-A1 (SH3GL2).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endophilin-A1 (SH3GL2).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Endophilin-A1 (SH3GL2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Endophilin-A1 (SH3GL2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Endophilin-A1 (SH3GL2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Endophilin-A1 (SH3GL2).	[23]
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⏷ Show the Full List of 6 Drug(s)

References

1	Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling.J Cell Mol Med. 2017 Nov;21(11):2685-2694. doi: 10.1111/jcmm.13184. Epub 2017 May 4.
2	Replication of top markers of a genome-wide association study in multiple sclerosis in Spain.Genes Immun. 2011 Mar;12(2):110-5. doi: 10.1038/gene.2010.52. Epub 2010 Oct 14.
3	The role of LINC00094/miR-224-5p (miR-497-5p)/Endophilin-1 axis in Memantine mediated protective effects on blood-brain barrier in AD microenvironment.J Cell Mol Med. 2019 May;23(5):3280-3292. doi: 10.1111/jcmm.14214. Epub 2019 Feb 22.
4	Endophilin 1 knockdown prevents synaptic dysfunction induced by oligomeric amyloid .Mol Med Rep. 2019 Jun;19(6):4897-4905. doi: 10.3892/mmr.2019.10158. Epub 2019 Apr 12.
5	Mitochondrial Reprogramming Regulates Breast Cancer Progression.Clin Cancer Res. 2016 Jul 1;22(13):3348-60. doi: 10.1158/1078-0432.CCR-15-2456. Epub 2016 Feb 17.
6	Frequent deletion and methylation in SH3GL2 and CDKN2A loci are associated with early- and late-onset breast carcinoma.Ann Surg Oncol. 2008 Apr;15(4):1070-80. doi: 10.1245/s10434-007-9790-0. Epub 2008 Feb 1.
7	Endophilin A1 mediates seizure activity via regulation of AMPARs in a PTZ-kindled epileptic mouse model.Exp Neurol. 2018 Jun;304:41-57. doi: 10.1016/j.expneurol.2018.02.014. Epub 2018 Feb 24.
8	SNP rs1049430 in the 3'-UTR of SH3GL2 regulates its expression: Clinical and prognostic implications in head and neck squamous cell carcinoma.Biochim Biophys Acta. 2015 May;1852(5):1059-67. doi: 10.1016/j.bbadis.2015.02.009. Epub 2015 Feb 26.
9	Aberrant promoter methylation of SH3GL2 gene in vulvar squamous cell carcinoma correlates with clinicopathological characteristics and HPV infection status.Int J Clin Exp Pathol. 2015 Nov 1;8(11):15442-7. eCollection 2015.
10	Study of the SH3-domain GRB2-like 2 gene expression in laryngeal carcinoma.Chin Med J (Engl). 2007 Mar 5;120(5):385-8.
11	SH3GL2 gene participates in MEK-ERK signal pathway partly by regulating EGFR in the laryngeal carcinoma cell line Hep2.Med Sci Monit. 2010 Jun;16(6):BR168-73.
12	SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.J Mol Med (Berl). 2013 Mar;91(3):381-93. doi: 10.1007/s00109-012-0955-3. Epub 2012 Sep 12.
13	Genetic basis of psychopathological dimensions shared between schizophrenia and bipolar disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:23-29. doi: 10.1016/j.pnpbp.2018.08.023. Epub 2018 Aug 24.
14	Loss of Sh3gl2/endophilin A1 is a common event in urothelial carcinoma that promotes malignant behavior.Neoplasia. 2013 Jul;15(7):749-60. doi: 10.1593/neo.121956.
15	Germline Genetic Biomarkers of Sunitinib Efficacy in Advanced Renal Cell Carcinoma: Results From the RENAL EFFECT Trial.Clin Genitourin Cancer. 2017 Oct;15(5):526-533. doi: 10.1016/j.clgc.2017.02.006. Epub 2017 Feb 27.
16	Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson's Disease.Trends Neurosci. 2019 Feb;42(2):140-149. doi: 10.1016/j.tins.2018.11.001. Epub 2018 Nov 30.
17	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.
18	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.
19	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
20	Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
21	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
22	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.
23	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.