Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2IVOK4)

• DOT Name: E3 ubiquitin-protein ligase SH3RF2 (SH3RF2)
• Synonyms: EC 2.3.2.27; Heart protein phosphatase 1-binding protein; HEPP1; POSH-eliminating RING protein; Protein phosphatase 1 regulatory subunit 39; RING finger protein 158; RING-type E3 ubiquitin transferase SH3RF2; SH3 domain-containing RING finger protein 2
• Gene Name: SH3RF2
• Related Disease: Acute myelogenous leukaemia
• UniProt ID: SH3R2_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00018 ; PF07653 ; PF14604 ; PF13639
• Sequence:
  MDDLTLLDLLECPVCFEKLDVTAKVLPCQHTFCKPCLQRVFKAHKELRCPECRTPVFSNI
  EALPANLLLVRLLDGVRSGQSSGRGGSFRRPGTMTLQDGRKSRTNPRRLQASPFRLVPNV
  RIHMDGVPRAKALCNYRGQNPGDLRFNKGDIILLRRQLDENWYQGEINGISGNFPASSVE
  VIKQLPQPPPLCRALYNFDLRGKDKSENQDCLTFLKDDIITVISRVDENWAEGKLGDKVG
  IFPILFVEPNLTARHLLEKNKGRQSSRTKNLSLVSSSSRGNTSTLRRGPGSRRKVPGQFS
  ITTALNTLNRMVHSPSGRHMVEISTPVLISSSNPSVITQPMEKADVPSSCVGQVSTYHPA
  PVSPGHSTAVVSLPGSQQHLSANMFVALHSYSAHGPDELDLQKGEGVRVLGKCQDGWLRG
  VSLVTGRVGIFPNNYVIPIFRKTSSFPDSRSPGLYTTWTLSTSSVSSQGSISEGDPRQSR
  PFKSVFVPTAIVNPVRSTAGPGTLGQGSLRKGRSSMRKNGSLQRPLQSGIPTLVVGSLRR
  SPTMVLRPQQFQFYQPQGIPSSPSAVVVEMGSKPALTGEPALTCISRGSEAWIHSAASSL
  IMEDKEIPIKSEPLPKPPASAPPSILVKPENSRNGIEKQVKTVRFQNYSPPPTKHYTSHP
  TSGKPEQPATLKASQPEAASLGPEMTVLFAHRSGCHSGQQTDLRRKSALGKATTLVSTAS
  GTQTVFPSK
• Function: Has E3 ubiquitin-protein ligase activity. Acts as an anti-apoptotic regulator of the JNK pathway by ubiquitinating and promoting the degradation of SH3RF1, a scaffold protein that is required for pro-apoptotic JNK activation. Facilitates TNF-alpha-mediated recruitment of adapter proteins TRADD and RIPK1 to TNFRSF1A and regulates PAK4 protein stability via inhibition of its ubiquitin-mediated proteasomal degradation. Inhibits PPP1CA phosphatase activity.
• Tissue Specificity: Heart (at protein level). Up-regulated in colon cancer tissues as compared to normal colon tissues (at protein level). Testis. In the heart, present in the apex, left atrium, right atrium, left ventricle and right ventricle, but not in the aorta.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[1]

14 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 E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[10]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase SH3RF2 (SH3RF2).	[15]

References

• [1] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [10] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] 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.