Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX6BOCN)

• DOT Name: Endophilin-A3 (SH3GL3)
• Synonyms: EEN-B2; Endophilin-3; SH3 domain protein 2C; SH3 domain-containing GRB2-like protein 3
• Gene Name: SH3GL3
• Related Disease:
  Colorectal carcinoma
  Adult glioblastoma
  Advanced cancer
  Childhood acute lymphoblastic leukemia
  Glioblastoma multiforme
  Glioma
  Huntington disease
  Malignant glioma
  Plasma cell myeloma
• UniProt ID: SH3G3_HUMAN
• PDB ID: 2EW3; 2Z0V
• Pfam ID: PF03114 ; PF00018
• Sequence:
  MSVAGLKKQFHKASQLFSEKISGAEGTKLDDEFLDMERKIDVTNKVVAEILSKTTEYLQP
  NPAYRAKLGMLNTVSKIRGQVKTTGYPQTEGLLGDCMLKYGKELGEDSTFGNALIEVGES
  MKLMAEVKDSLDINVKQTFIDPLQLLQDKDLKEIGHHLKKLEGRRLDYDYKKKRVGKIPD
  EEVRQAVEKFEESKELAERSMFNFLENDVEQVSQLAVFIEAALDYHRQSTEILQELQSKL
  QMRISAASSVPRREYKPRPVKRSSSELNGVSTTSVVKTTGSNIPMDQPCCRGLYDFEPEN
  QGELGFKEGDIITLTNQIDENWYEGMIHGESGFFPINYVEVIVPLPQ
• Function: Implicated in endocytosis. May recruit other proteins to membranes with high curvature.
• Tissue Specificity: Brain and testis.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  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)
  NGF-stimulated transcription (R-HSA-9031628)
  EGFR downregulation (R-HSA-182971)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Huntington disease	DISQPLA4	Strong	Biomarker	[6]
Malignant glioma	DISFXKOV	Strong	Biomarker	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[7]

7 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 Endophilin-A3 (SH3GL3).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Endophilin-A3 (SH3GL3).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Endophilin-A3 (SH3GL3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Endophilin-A3 (SH3GL3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Endophilin-A3 (SH3GL3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Endophilin-A3 (SH3GL3).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Endophilin-A3 (SH3GL3).	[16]

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 Endophilin-A3 (SH3GL3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Endophilin-A3 (SH3GL3).	[14]

References

• [1] Genome-wide analysis of aberrant DNA methylation for identification of potential biomarkers in colorectal cancer patients.Asian Pac J Cancer Prev. 2012;13(5):1917-21. doi: 10.7314/apjcp.2012.13.5.1917.
• [2] Molecular mechanisms underlying gliomas and glioblastoma pathogenesis revealed by bioinformatics analysis of microarray data.Med Oncol. 2017 Sep 26;34(11):182. doi: 10.1007/s12032-017-1043-x.
• [3] Competition between TIAM1 and Membranes Balances Endophilin A3 Activity in Cancer Metastasis.Dev Cell. 2018 Jun 18;45(6):738-752.e6. doi: 10.1016/j.devcel.2018.05.021.
• [4] Maternal Red Blood Cell Folate and Infant Vitamin B(12) Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia.Mol Nutr Food Res. 2018 Nov;62(22):e1800411. doi: 10.1002/mnfr.201800411. Epub 2018 Oct 11.
• [5] Identification and functional validation of CDH11, PCSK6 and SH3GL3 as novel glioma invasion-associated candidate genes.Neuropathol Appl Neurobiol. 2012 Apr;38(2):201-12. doi: 10.1111/j.1365-2990.2011.01207.x.
• [6] SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates.Mol Cell. 1998 Oct;2(4):427-36. doi: 10.1016/s1097-2765(00)80142-2.
• [7] The role of SH3GL3 in myeloma cell migration/invasion, stemness and chemo-resistance.Oncotarget. 2016 Nov 8;7(45):73101-73113. doi: 10.18632/oncotarget.12231.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.