Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGED7Z2)

• DOT Name: SH3 domain-binding protein 1 (SH3BP1)
• Gene Name: SH3BP1
• Related Disease:
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Hypoglycemia
  Type-1/2 diabetes
• UniProt ID: 3BP1_HUMAN
• PDB ID: 4J9D; 4J9F
• Pfam ID: PF03114 ; PF00620
• Sequence:
  MMKRQLHRMRQLAQTGSLGRTPETAEFLGEDLLQVEQRLEPAKRAAHNIHKRLQACLQGQ
  SGADMDKRVKKLPLMALSTTMAESFKELDPDSSMGKALEMSCAIQNQLARILAEFEMTLE
  RDVLQPLSRLSEEELPAILKHKKSLQKLVSDWNTLKSRLSQATKNSGSSQGLGGSPGSHS
  HTTMANKVETLKEEEEELKRKVEQCRDEYLADLYHFVTKEDSYANYFIRLLEIQADYHRR
  SLSSLDTALAELRENHGQADHSPSMTATHFPRVYGVSLATHLQELGREIALPIEACVMML
  LSEGMKEEGLFRLAAGASVLKRLKQTMASDPHSLEEFCSDPHAVAGALKSYLRELPEPLM
  TFDLYDDWMRAASLKEPGARLQALQEVCSRLPPENLSNLRYLMKFLARLAEEQEVNKMTP
  SNIAIVLGPNLLWPPEKEGDQAQLDAASVSSIQVVGVVEALIQSADTLFPGDINFNVSGL
  FSAVTLQDTVSDRLASEELPSTAVPTPATTPAPAPAPAPAPAPALASAATKERTESEVPP
  RPASPKVTRSPPETAAPVEDMARRTKRPAPARPTMPPPQVSGSRSSPPAPPLPPGSGSPG
  TPQALPRRLVGSSLRAPTVPPPLPPTPPQPARRQSRRSPASPSPASPGPASPSPVSLSNP
  AQVDLGAATAEGGAPEAISGVPTPPAIPPQPRPRSLASETN
• Function: GTPase activating protein (GAP) which specifically converts GTP-bound Rho-type GTPases including RAC1 and CDC42 in their inactive GDP-bound form. By specifically inactivating RAC1 at the leading edge of migrating cells, it regulates the spatiotemporal organization of cell protrusions which is important for proper cell migration. Also negatively regulates CDC42 in the process of actin remodeling and the formation of epithelial cell junctions. Through its GAP activity toward RAC1 and/or CDC42 plays a specific role in phagocytosis of large particles. Specifically recruited by a PI3 kinase/PI3K-dependent mechanism to sites of large particles engagement, inactivates RAC1 and/or CDC42 allowing the reorganization of the underlying actin cytoskeleton required for engulfment. It also plays a role in angiogenesis and the process of repulsive guidance as part of a semaphorin-plexin signaling pathway. Following the binding of PLXND1 to extracellular SEMA3E it dissociates from PLXND1 and inactivates RAC1, inducing the intracellular reorganization of the actin cytoskeleton and the collapse of cells.
• Reactome Pathway: RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[1]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SH3 domain-binding protein 1 (SH3BP1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of SH3 domain-binding protein 1 (SH3BP1).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH3 domain-binding protein 1 (SH3BP1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SH3 domain-binding protein 1 (SH3BP1).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of SH3 domain-binding protein 1 (SH3BP1).	[10]

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 increases the methylation of SH3 domain-binding protein 1 (SH3BP1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of SH3 domain-binding protein 1 (SH3BP1).	[9]

References

• [1] SH3BP1-induced Rac-Wave2 pathway activation regulates cervical cancer cell migration, invasion, and chemoresistance to cisplatin.J Cell Biochem. 2018 Feb;119(2):1733-1745. doi: 10.1002/jcb.26334. Epub 2017 Sep 18.
• [2] SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway.Oncotarget. 2016 Apr 5;7(14):18356-70. doi: 10.18632/oncotarget.7786.
• [3] Regulated hepatic insulin gene therapy of STZ-diabetic rats.Gene Ther. 2000 Oct;7(20):1744-52. doi: 10.1038/sj.gt.3301297.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.