Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXY5RXC)

• DOT Name: Signal-induced proliferation-associated protein 1 (SIPA1)
• Synonyms: Sipa-1; GTPase-activating protein Spa-1; p130 SPA-1
• Gene Name: SIPA1
• Related Disease:
  Coronary heart disease
  Invasive breast carcinoma
  Advanced cancer
  Anemia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Bronchopulmonary dysplasia
  Childhood myelodysplastic syndrome
  Colorectal carcinoma
  Craniosynostosis
  Cystic fibrosis
  Estrogen-receptor positive breast cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Metastatic malignant neoplasm
  Multiple endocrine neoplasia type 1
  Myelodysplastic syndrome
  Myelodysplastic/myeloproliferative neoplasm
  Nasal polyp
  Non-small-cell lung cancer
  Prostate cancer
  Squamous cell carcinoma
  Gastric cancer
  Methicillin-resistant staphylococci infection
  Stomach cancer
  T-cell immunodeficiency
  Breast neoplasm
  Neoplasm
• UniProt ID: SIPA1_HUMAN
• Pfam ID: PF00595 ; PF21022 ; PF02145
• Sequence:
  MPMWAGGVGSPRRGMAPASTDDLFARKLRQPARPPLTPHTFEPRPVRGPLLRSGSDAGEA
  RPPTPASPRARAHSHEEASRPAATSTRLFTDPLALLGLPAEEPEPAFPPVLEPRWFAHYD
  VQSLLFDWAPRSQGMGSHSEASSGTLASAEDQAASSDLLHGAPGFVCELGGEGELGLGGP
  ASPPVPPALPNAAVSILEEPQNRTSAYSLEHADLGAGYYRKYFYGKEHQNFFGMDESLGP
  VAVSLRREEKEGSGGGTLHSYRVIVRTTQLRTLRGTISEDALPPGPPRGLSPRKLLEHVA
  PQLSPSCLRLGSASPKVPRTLLTLDEQVLSFQRKVGILYCRAGQGSEEEMYNNQEAGPAF
  MQFLTLLGDVVRLKGFESYRAQLDTKTDSTGTHSLYTTYQDHEIMFHVSTMLPYTPNNQQ
  QLLRKRHIGNDIVTIVFQEPGSKPFCPTTIRSHFQHVFLVVRAHTPCTPHTTYRVAVSRT
  QDTPAFGPALPAGGGPFAANADFRAFLLAKALNGEQAAGHARQFHAMATRTRQQYLQDLA
  TNEVTTTSLDSASRFGLPSLGGRRRAAPRGPGAELQAAGSLVWGVRAAPGARVAAGAQAS
  GPEGIEVPCLLGISAEALVLVAPRDGRVVFNCACRDVLAWTFSEQQLDLYHGRGEAITLR
  FDGSPGQAVGEVVARLQLVSRGCETRELALPRDGQGRLGFEVDAEGFVTHVERFTFAETA
  GLRPGARLLRVCGQTLPSLRPEAAAQLLRSAPKVCVTVLPPDESGRPRRSFSELYTLSLQ
  EPSRRGAPDPVQDEVQGVTLLPTTKQLLHLCLQDGGSPPGPGDLAEERTEFLHSQNSLSP
  RSSLSDEAPVLPNTTPDLLLATTAKPSVPSADSETPLTQDRPGSPSGSEDKGNPAPELRA
  SFLPRTLSLRNSISRIMSEAGSGTLEDEWQAISEIASTCNTILESLSREGQPIPESGDPK
  GTPKSDAEPEPGNLSEKVSHLESMLRKLQEDLQKEKADRAALEEEVRSLRHNNRRLQAES
  ESAATRLLLASKQLGSPTADLA
• Function: GTPase activator for the nuclear Ras-related regulatory proteins Rap1 and Rap2 in vitro, converting them to the putatively inactive GDP-bound state. Affects cell cycle progression.
• Tissue Specificity: Expressed in fetal as well as in adult tissues. Expressed abundantly in the lymphoid tissues such as thymus, spleen and peripheral blood lymphocytes and also shows a significant expression in the spinal cord.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Leukocyte transendothelial migration (hsa04670)
• Reactome Pathway: Rap1 signalling (R-HSA-392517)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Invasive breast carcinoma	DISANYTW	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Anemia	DISTVL0C	Strong	Biomarker	[4]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[4]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Genetic Variation	[5]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Craniosynostosis	DIS6J405	Strong	Biomarker	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[9]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[9]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[11]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[12]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[4]
Myelodysplastic/myeloproliferative neoplasm	DISDHXQ4	Strong	Genetic Variation	[13]
Nasal polyp	DISLP3XE	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[15]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Genetic Variation	[16]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[15]
T-cell immunodeficiency	DISHMPS5	moderate	Biomarker	[17]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[18]
Neoplasm	DISZKGEW	Limited	Altered Expression	[15]

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 Signal-induced proliferation-associated protein 1 (SIPA1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Signal-induced proliferation-associated protein 1 (SIPA1).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Signal-induced proliferation-associated protein 1 (SIPA1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Signal-induced proliferation-associated protein 1 (SIPA1).	[28]

8 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 Signal-induced proliferation-associated protein 1 (SIPA1).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[24]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Signal-induced proliferation-associated protein 1 (SIPA1).	[27]

References

• [1] Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci.Am J Hum Genet. 2018 Sep 6;103(3):377-388. doi: 10.1016/j.ajhg.2018.08.001. Epub 2018 Aug 23.
• [2] Nuclear SIPA1 activates integrin 1 promoter and promotes invasion of breast cancer cells.Oncogene. 2015 Mar 12;34(11):1451-62. doi: 10.1038/onc.2014.36. Epub 2014 Apr 7.
• [3] SIPA1 promotes invasion and migration in human oral squamous cell carcinoma by ITGB1 and MMP7.Exp Cell Res. 2017 Mar 15;352(2):357-363. doi: 10.1016/j.yexcr.2017.02.026. Epub 2017 Feb 22.
• [4] Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice.Cancer Cell. 2003 Jul;4(1):55-65. doi: 10.1016/s1535-6108(03)00163-6.
• [5] Dysplasia: a review.Pediatr Pulmonol. 2007 Oct;42(10):952-61. doi: 10.1002/ppul.20689.
• [6] Expression of signal-induced proliferation-associated gene 1 (SIPA1), a RapGTPase-activating protein, is increased in colorectal cancer and has diverse effects on functions of colorectal cancer cells.Cancer Genomics Proteomics. 2012 Sep-Oct;9(5):321-7.
• [7] Sinonasal surfactant protein A1, A2, and D gene expression in cystic fibrosis: a preliminary report.Otolaryngol Head Neck Surg. 2007 Jul;137(1):34-8. doi: 10.1016/j.otohns.2007.01.025.
• [8] Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and estrogen receptor status, in women with European and African ancestry.Mol Carcinog. 2017 Mar;56(3):1000-1009. doi: 10.1002/mc.22565. Epub 2016 Sep 21.
• [9] Sipa1 promoter polymorphism predicts risk and metastasis of lung cancer in Chinese.Mol Carcinog. 2013 Nov;52 Suppl 1:E110-7. doi: 10.1002/mc.22039. Epub 2013 May 9.
• [10] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [11] Polymorphisms in MMP9 and SIPA1 are associated with increased risk of nodal metastases in early-stage cervical cancer.Gynecol Oncol. 2010 Mar;116(3):539-43. doi: 10.1016/j.ygyno.2009.09.037. Epub 2009 Nov 10.
• [12] Genomic organization and cloning of the human homologue of murine Sipa-1.Gene. 1998 Jul 3;214(1-2):215-21. doi: 10.1016/s0378-1119(98)00212-1.
• [13] Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm.Blood Adv. 2018 Mar 13;2(5):534-548. doi: 10.1182/bloodadvances.2017013599.
• [14] The SIPA1 -313A>G polymorphism is associated with prognosis in inoperable non-small cell lung cancer.Tumour Biol. 2015 Feb;36(2):1273-8. doi: 10.1007/s13277-014-2753-8. Epub 2014 Oct 29.
• [15] Dynamic relationship between SIPA1 gene and protein expression and the development of gastric cancer.Genet Mol Res. 2017 Mar 16;16(1). doi: 10.4238/gmr16019271.
• [16] Nosocomial outbreak of multidrug-resistant USA300 methicillin-resistant Staphylococcus aureus causing severe furuncles and carbuncles in Japan.J Dermatol. 2011 Dec;38(12):1167-71. doi: 10.1111/j.1346-8138.2011.01284.x. Epub 2011 Oct 18.
• [17] Rap1 and SPA-1 in hematologic malignancy.Trends Mol Med. 2004 Aug;10(8):401-8. doi: 10.1016/j.molmed.2004.06.004.
• [18] Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival.Breast Cancer Res Treat. 2013 Jun;139(3):873-85. doi: 10.1007/s10549-013-2601-3. Epub 2013 Jun 16.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] 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.
• [26] 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.
• [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.