Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ8NPAW)

• DOT Name: Spermatogenesis-associated protein 13 (SPATA13)
• Synonyms: APC-stimulated guanine nucleotide exchange factor 2; Asef2
• Gene Name: SPATA13
• Related Disease:
  Adenoma
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Breast neoplasm
  Colorectal neoplasm
  Differentiated thyroid carcinoma
  Hypothyroidism
  STAT3-related early-onset multisystem autoimmune disease
  Primary angle-closure glaucoma
• UniProt ID: SPT13_HUMAN
• Pfam ID: PF00169 ; PF00621 ; PF00018
• Sequence:
  MTSASPEDQNAPVGCPKGARRRRPISVIGGVSLYGTNQTEELDNLLTQPASRPPMPAHQV
  PPYKAVSARFRPFTFSQSTPIGLDRVGRRRQMRASNVSSDGGTEPSALVDDNGSEEDFSY
  EDLCQASPRYLQPGGEQLAINELISDGNVVCAEALWDHVTMDDQELGFKAGDVIQVLEAS
  NKDWWWGRSEDKEAWFPASFVRLRVNQEELSENSSSTPSEEQDEEASQSRHRHCENKQQM
  RTNVIREIMDTERVYIKHLRDICEGYIRQCRKHTGMFTVAQLATIFGNIEDIYKFQRKFL
  KDLEKQYNKEEPHLSEIGSCFLQNQEGFAIYSEYCNNHPGACLELANLMKQGKYRHFFEA
  CRLLQQMIDIAIDGFLLTPVQKICKYPLQLAELLKYTTQEHGDYSNIKAAYEAMKNVACL
  INERKRKLESIDKIARWQVSIVGWEGLDILDRSSELIHSGELTKITKQGKSQQRTFFLFD
  HQLVSCKKDLLRRDMLYYKGRLDMDEMELVDLGDGRDKDCNLSVKNAFKLVSRTTDEVYL
  FCAKKQEDKARWLQACADERRRVQEDKEMGMEISENQKKLAMLNAQKAGHGKSKGYNRCP
  VAPPHQGLHPIHQRHITMPTSVPQQQVFGLAEPKRKSSLFWHTFNRLTPFRK
• Function: Acts as a guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Regulates cell migration and adhesion assembly and disassembly through a RAC1, PI3K, RHOA and AKT1-dependent mechanism. Increases both RAC1 and CDC42 activity, but decreases the amount of active RHOA. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.
• Tissue Specificity: Expressed at high levels in the placenta, spleen and kidney, at moderate levels in lung, small intestine, liver, brain and heart, and at low levels in skeletal muscle. Expression is aberrantly enhanced in most colorectal tumors.
• KEGG Pathway: Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Genetic Variation	[5]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]
Primary angle-closure glaucoma	DISX8UKZ	Limited	Autosomal dominant	[6]

4 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 Spermatogenesis-associated protein 13 (SPATA13).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Spermatogenesis-associated protein 13 (SPATA13).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Spermatogenesis-associated protein 13 (SPATA13).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Spermatogenesis-associated protein 13 (SPATA13).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Spermatogenesis-associated protein 13 (SPATA13).	[21]

References

• [1] The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in Apc(Min/+)mice.EMBO Rep. 2009 Dec;10(12):1355-62. doi: 10.1038/embor.2009.233. Epub 2009 Nov 6.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Genome-wide DNA methylation assessment of 'BRCA1-like' early-onset breast cancer: Data from the Australian Breast Cancer Family Registry.Exp Mol Pathol. 2018 Dec;105(3):404-410. doi: 10.1016/j.yexmp.2018.11.006. Epub 2018 Nov 10.
• [4] Identification and characterization of Asef2, a guanine-nucleotide exchange factor specific for Rac1 and Cdc42.Oncogene. 2007 Dec 6;26(55):7620-267. doi: 10.1038/sj.onc.1210574. Epub 2007 Jun 18.
• [5] Novel genome-wide association study-based candidate loci for differentiated thyroid cancer risk.J Clin Endocrinol Metab. 2014 Oct;99(10):E2084-92. doi: 10.1210/jc.2014-1734. Epub 2014 Jul 16.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Differential regulation of native estrogen receptor-regulatory elements by estradiol, tamoxifen, and raloxifene. Mol Endocrinol. 2008 Feb;22(2):287-303. doi: 10.1210/me.2007-0340. Epub 2007 Oct 25.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [15] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.