Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJSX44Y)

• DOT Name: Sorbin and SH3 domain-containing protein 2 (SORBS2)
• Synonyms: Arg-binding protein 2; ArgBP2; Arg/Abl-interacting protein 2; Sorbin
• Gene Name: SORBS2
• Related Disease:
  Hepatocellular carcinoma
  Abetalipoproteinemia
  Advanced cancer
  Alzheimer disease
  Breast fibrocystic disease
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Neoplasm
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Pancreatic tumour
• UniProt ID: SRBS2_HUMAN
• PDB ID: 5VEI
• Pfam ID: PF00018 ; PF14604 ; PF02208
• Sequence:
  MSYYQRPFSPSAYSLPASLNSSIVMQHGTSLDSTDTYPQHAQSLDGTTSSSIPLYRSSEE
  EKRVTVIKAPHYPGIGPVDESGIPTAIRTTVDRPKDWYKTMFKQIHMVHKPDDDTDMYNT
  PYTYNAGLYNPPYSAQSHPAAKTQTYRPLSKSHSDNSPNAFKDASSPVPPPHVPPPVPPL
  RPRDRSSTEKHDWDPPDRKVDTRKFRSEPRSIFEYEPGKSSILQHERPASLYQSSIDRSL
  ERPMSSASMASDFRKRRKSEPAVGPPRGLGDQSASRTSPGRVDLPGSSTTLTKSFTSSSP
  SSPSRAKGGDDSKICPSLCSYSGLNGNPSSELDYCSTYRQHLDVPRDSPRAISFKNGWQM
  ARQNAEIWSSTEETVSPKIKSRSCDDLLNDDCDSFPDPKVKSESMGSLLCEEDSKESCPM
  AWGSPYVPEVRSNGRSRIRHRSARNAPGFLKMYKKMHRINRKDLMNSEVICSVKSRILQY
  ESEQQHKDLLRAWSQCSTEEVPRDMVPTRISEFEKLIQKSKSMPNLGDDMLSPVTLEPPQ
  NGLCPKRRFSIEYLLEEENQSGPPARGRRGCQSNALVPIHIEVTSDEQPRAHVEFSDSDQ
  DGVVSDHSDYIHLEGSSFCSESDFDHFSFTSSESFYGSSHHHHHHHHHHHRHLISSCKGR
  CPASYTRFTTMLKHERARHENTEEPRRQEMDPGLSKLAFLVSPVPFRRKKNSAPKKQTEK
  AKCKASVFEALDSALKDICDQIKAEKKRGSLPDNSILHRLISELLPDVPERNSSLRALRR
  SPLHQPLHPLPPDGAIHCPPYQNDCGRMPRSASFQDVDTANSSCHHQDRGGALQDRESPR
  SYSSTLTDMGRSAPRERRGTPEKEKLPAKAVYDFKAQTSKELSFKKGDTVYILRKIDQNW
  YEGEHHGRVGIFPISYVEKLTPPEKAQPARPPPPAQPGEIGEAIAKYNFNADTNVELSLR
  KGDRVILLKRVDQNWYEGKIPGTNRQGIFPVSYVEVVKKNTKGAEDYPDPPIPHSYSSDR
  IHSLSSNKPQRPVFTHENIQGGGEPFQALYNYTPRNEDELELRESDVIDVMEKCDDGWFV
  GTSRRTKFFGTFPGNYVKRL
• Function: Adapter protein that plays a role in the assembling of signaling complexes, being a link between ABL kinases and actin cytoskeleton. Can form complex with ABL1 and CBL, thus promoting ubiquitination and degradation of ABL1. May play a role in the regulation of pancreatic cell adhesion, possibly by acting on WASF1 phosphorylation, enhancing phosphorylation by ABL1, as well as dephosphorylation by PTPN12. Isoform 6 increases water and sodium absorption in the intestine and gall-bladder.
• Tissue Specificity: Abundantly expressed in heart. In cardiac muscle cells, located in the Z-disks of sarcomere. Also found, but to a lower extent, in small and large intestine, pancreas, thymus, colon, spleen, prostate, testis, brain, ovary and epithelial cells. In the pancreas, mainly expressed in acinar cells, duct cells and all cell types in islets (at protein level). Tends to be down-regulated in pancreatic adenocarcinomas ans metastases.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Abetalipoproteinemia	DISMSS7T	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Breast fibrocystic disease	DISUM7ID	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Biomarker	[8]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Sorbin and SH3 domain-containing protein 2 (SORBS2) affects the response to substance of Etoposide.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[17]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[19]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[20]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[21]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[30]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Sorbin and SH3 domain-containing protein 2 (SORBS2).	[31]

References

• [1] The RNA-binding protein SORBS2 suppresses hepatocellular carcinoma tumourigenesis and metastasis by stabilizing RORA mRNA.Liver Int. 2019 Nov;39(11):2190-2203. doi: 10.1111/liv.14202. Epub 2019 Sep 25.
• [2] ArgBP2-dependent signaling regulates pancreatic cell migration, adhesion, and tumorigenicity.Cancer Res. 2008 Jun 15;68(12):4588-96. doi: 10.1158/0008-5472.CAN-08-0958.
• [3] The RNA binding protein SORBS2 suppresses metastatic colonization of ovarian cancer by stabilizing tumor-suppressive immunomodulatory transcripts.Genome Biol. 2018 Mar 16;19(1):35. doi: 10.1186/s13059-018-1412-6.
• [4] Whole-Transcriptome Analysis of APP/PS1 Mouse Brain and Identification of circRNA-miRNA-mRNA Networks to Investigate AD Pathogenesis.Mol Ther Nucleic Acids. 2019 Dec 6;18:1049-1062. doi: 10.1016/j.omtn.2019.10.030. Epub 2019 Nov 6.
• [5] NanoString-based breast cancer risk prediction for women with sclerosing adenosis.Breast Cancer Res Treat. 2017 Nov;166(2):641-650. doi: 10.1007/s10549-017-4441-z. Epub 2017 Aug 10.
• [6] Genome-wide gene expression profile analyses identify CTTN as a potential prognostic marker in esophageal cancer.PLoS One. 2014 Feb 14;9(2):e88918. doi: 10.1371/journal.pone.0088918. eCollection 2014.
• [7] Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.Lancet. 2012 Sep 1;380(9844):815-23. doi: 10.1016/S0140-6736(12)60681-3. Epub 2012 Jul 3.
• [8] CIP4 is a new ArgBP2 interacting protein that modulates the ArgBP2 mediated control of WAVE1 phosphorylation and cancer cell migration.Cancer Lett. 2010 Feb 1;288(1):116-23. doi: 10.1016/j.canlet.2009.06.030. Epub 2009 Jul 23.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] 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.
• [21] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [22] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [25] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [32] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.