Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPG2D8Z)

• DOT Name: Tensin-3 (TNS3)
• Synonyms: EC 3.1.3.-; Tensin-like SH2 domain-containing protein 1; Tumor endothelial marker 6
• Gene Name: TNS3
• Related Disease:
  Alzheimer disease
  Breast carcinoma
  Chromosomal disorder
  Clear cell renal carcinoma
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Hepatocellular carcinoma
  IgA nephropathy
  Maple syrup urine disease
  Matthew-Wood syndrome
  Pancreatic cancer
  Prostate carcinoma
  Renal cell carcinoma
  Skin and skin-structure infection
  Triple negative breast cancer
  Advanced cancer
  Breast cancer
  Congenital thrombotic thrombocytopenic purpura
  Glioblastoma multiforme
  Thyrotoxicosis
  Basal cell carcinoma
  Basal cell neoplasm
• UniProt ID: TENS3_HUMAN
• EC Number: 3.1.3.-
• Pfam ID: PF08416 ; PF10409 ; PF00017
• Sequence:
  MEEGHGLDLTYITERIIAVSFPAGCSEESYLHNLQEVTRMLKSKHGDNYLVLNLSEKRYD
  LTKLNPKIMDVGWPELHAPPLDKMCTICKAQESWLNSNLQHVVVIHCRGGKGRIGVVISS
  YMHFTNVSASADQALDRFAMKKFYDDKVSALMQPSQKRYVQFLSGLLSGSVKMNASPLFL
  HFVILHGTPNFDTGGVCRPFLKLYQAMQPVYTSGIYNVGPENPSRICIVIEPAQLLKGDV
  MVKCYHKKYRSATRDVIFRLQFHTGAVQGYGLVFGKEDLDNASKDDRFPDYGKVELVFSA
  TPEKIQGSEHLYNDHGVIVDYNTTDPLIRWDSYENLSADGEVLHTQGPVDGSLYAKVRKK
  SSSDPGIPGGPQAIPATNSPDHSDHTLSVSSDSGHSTASARTDKTEERLAPGTRRGLSAQ
  EKAELDQLLSGFGLEDPGSSLKEMTDARSKYSGTRHVVPAQVHVNGDAALKDRETDILDD
  EMPHHDLHSVDSLGTLSSSEGPQSAHLGPFTCHKSSQNSLLSDGFGSNVGEDPQGTLVPD
  LGLGMDGPYERERTFGSREPKQPQPLLRKPSVSAQMQAYGQSSYSTQTWVRQQQMVVAHQ
  YSFAPDGEARLVSRCPADNPGLVQAQPRVPLTPTRGTSSRVAVQRGVGSGPHPPDTQQPS
  PSKAFKPRFPGDQVVNGAGPELSTGPSPGSPTLDIDQSIEQLNRLILELDPTFEPIPTHM
  NALGSQANGSVSPDSVGGGLRASSRLPDTGEGPSRATGRQGSSAEQPLGGRLRKLSLGQY
  DNDAGGQLPFSKCAWGKAGVDYAPNLPPFPSPADVKETMTPGYPQDLDIIDGRILSSKES
  MCSTPAFPVSPETPYVKTALRHPPFSPPEPPLSSPASQHKGGREPRSCPETLTHAVGMSE
  SPIGPKSTMLRADASSTPSFQQAFASSCTISSNGPGQRRESSSSAERQWVESSPKPMVSL
  LGSGRPTGSPLSAEFSGTRKDSPVLSCFPPSELQAPFHSHELSLAEPPDSLAPPSSQAFL
  GFGTAPVGSGLPPEEDLGALLANSHGASPTPSIPLTATGAADNGFLSHNFLTVAPGHSSH
  HSPGLQGQGVTLPGQPPLPEKKRASEGDRSLGSVSPSSSGFSSPHSGSTISIPFPNVLPD
  FSKASEAASPLPDSPGDKLVIVKFVQDTSKFWYKADISREQAIAMLKDKEPGSFIVRDSH
  SFRGAYGLAMKVATPPPSVLQLNKKAGDLANELVRHFLIECTPKGVRLKGCSNEPYFGSL
  TALVCQHSITPLALPCKLLIPERDPLEEIAESSPQTAANSAAELLKQGAACNVWYLNSVE
  MESLTGHQAIQKALSITLVQEPPPVSTVVHFKVSAQGITLTDNQRKLFFRRHYPVNSVIF
  CALDPQDRKWIKDGPSSKVFGFVARKQGSATDNVCHLFAEHDPEQPASAIVNFVSKVMIG
  SPKKV
• Function: May act as a protein phosphatase and/or a lipid phosphatase (Probable). Involved in the dissociation of the integrin-tensin-actin complex. EGF activates TNS4 and down-regulates TNS3 which results in capping the tail of ITGB1. Increases DOCK5 guanine nucleotide exchange activity towards Rac and plays a role in osteoclast podosome organization. Enhances RHOA activation in the presence of DLC1. Required for growth factor-induced epithelial cell migration; growth factor stimulation induces TNS3 phosphorylation which changes its binding preference from DLC1 to the p85 regulatory subunit of the PI3K kinase complex, displacing PI3K inhibitor PTEN and resulting in translocation of the TNS3-p85 complex to the leading edge of migrating cells to promote RAC1 activation. Meanwhile, PTEN switches binding preference from p85 to DLC1 and the PTEN-DLC1 complex translocates to the posterior of migrating cells to activate RHOA. Acts as an adapter protein by bridging the association of scaffolding protein PEAK1 with integrins ITGB1, ITGB3 and ITGB5 which contributes to the promotion of cell migration. Controls tonsil-derived mesenchymal stem cell proliferation and differentiation by regulating the activity of integrin ITGB1.
• Tissue Specificity: Expressed in umbilical vein endothelial cells, epithelial cells, and fibroblasts cells (at protein level). Highly expressed in thyroid, kidney and placenta. Low expression in heart, skeletal muscle, spleen, liver, and lung. Expressed at higher levels in tonsil-derived mesenchymal stem cells (MSCs) than in adipose tissue-derived MSCs or bone marrow-derived MSCs . Expressed in tumor endothelial cells. Expression seems to be down-regulated in thyroid tumor tissues and in anaplastic carcinomas.
• Reactome Pathway: MET interacts with TNS proteins (R-HSA-8875513)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Genetic Variation	[5]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[5]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[7]
Maple syrup urine disease	DIS61XRH	Strong	Biomarker	[8]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[9]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[10]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[11]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[4]
Skin and skin-structure infection	DIS3F9EY	Strong	Biomarker	[12]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[13]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[14]
Breast cancer	DIS7DPX1	moderate	Biomarker	[2]
Congenital thrombotic thrombocytopenic purpura	DISC8GS9	moderate	Biomarker	[15]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[16]
Thyrotoxicosis	DISWH7BV	moderate	Biomarker	[17]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[18]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Tensin-3 (TNS3) affects the response to substance of Fluorouracil.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Tensin-3 (TNS3).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tensin-3 (TNS3).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tensin-3 (TNS3).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tensin-3 (TNS3).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tensin-3 (TNS3).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tensin-3 (TNS3).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tensin-3 (TNS3).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tensin-3 (TNS3).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tensin-3 (TNS3).	[28]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Tensin-3 (TNS3).	[30]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Tensin-3 (TNS3).	[31]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Tensin-3 (TNS3).	[32]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Tensin-3 (TNS3).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tensin-3 (TNS3).	[34]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tensin-3 (TNS3).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tensin-3 (TNS3).	[36]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Tensin-3 (TNS3).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tensin-3 (TNS3).	[38]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of Tensin-3 (TNS3).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Tensin-3 (TNS3).	[26]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Tensin-3 (TNS3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tensin-3 (TNS3).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Tensin-3 (TNS3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Tensin-3 (TNS3).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Tensin-3 (TNS3).	[26]

References

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