Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCCGY2K)

DOT Name	Transmembrane protease serine 4 (TMPRSS4)
Synonyms	EC 3.4.21.-; Channel-activating protease 2; CAPH2; Membrane-type serine protease 2; MT-SP2
Gene Name	TMPRSS4
Related Disease	Lung adenocarcinoma ( ) Thyroid gland papillary carcinoma ( ) Advanced cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Carcinoma of esophagus ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Esophageal squamous cell carcinoma ( ) Gastric cancer ( ) Hepatocellular carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lung neoplasm ( ) Matthew-Wood syndrome ( ) Non-small-cell lung cancer ( ) Prostate cancer ( ) Prostate carcinoma ( ) Pulmonary fibrosis ( ) Stomach cancer ( ) Thyroid cancer ( ) Autosomal recessive cerebral atrophy ( ) Thyroid gland carcinoma ( ) Thyroid tumor ( ) Epithelial ovarian cancer ( ) Gallbladder cancer ( ) Gallbladder carcinoma ( ) Ovarian cancer ( ) Ovarian neoplasm ( )
UniProt ID	TMPS4_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
EC Number	3.4.21.-
Pfam ID	PF15494 ; PF00089
Sequence	MLQDPDSDQPLNSLDVKPLRKPRIPMETFRKVGIPIIIALLSLASIIIVVVLIKVILDKY YFLCGQPLHFIPRKQLCDGELDCPLGEDEEHCVKSFPEGPAVAVRLSKDRSTLQVLDSAT GNWFSACFDNFTEALAETACRQMGYSSKPTFRAVEIGPDQDLDVVEITENSQELRMRNSS GPCLSGSLVSLHCLACGKSLKTPRVVGVEEASVDSWPWQVSIQYDKQHVCGGSILDPHWV LTAAHCFRKHTDVFNWKVRAGSDKLGSFPSLAVAKIIIIEFNPMYPKDNDIALMKLQFPL TFSGTVRPICLPFFDEELTPATPLWIIGWGFTKQNGGKMSDILLQASVQVIDSTRCNADD AYQGEVTEKMMCAGIPEGGVDTCQGDSGGPLMYQSDQWHVVGIVSWGYGCGGPSTPGVYT KVSAYLNWIYNVWKAEL
Function	Plasma membrane-anchored serine protease that directly induces processing of pro-uPA/PLAU into the active form through proteolytic activity. Seems to be capable of activating ENaC; (Microbial infection) In gut epithelial cells, facilitates human coronavirus SARS-CoV-2 infection through, at least, the cleavage of coronavirus spike glycoproteins which activates the glycoprotein for host cell entry.
Tissue Specificity	High levels in pancreatic, gastric, colorectal and ampullary cancer. Very weak expression in normal gastrointestinal and urogenital tract . Coexpressed with ACE2 within mature enterocytes .
KEGG Pathway	Influenza A (hsa05164 )

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[9]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[11]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[13]
Autosomal recessive cerebral atrophy	DISYFTHR	Supportive	Autosomal recessive	[14]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Altered Expression	[13]
Thyroid tumor	DISLVKMD	Disputed	Altered Expression	[13]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[15]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[16]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[16]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[15]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[15]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transmembrane protease serine 4 (TMPRSS4).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane protease serine 4 (TMPRSS4).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transmembrane protease serine 4 (TMPRSS4).	[19]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Transmembrane protease serine 4 (TMPRSS4).	[20]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Transmembrane protease serine 4 (TMPRSS4).	[21]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of Transmembrane protease serine 4 (TMPRSS4).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Transmembrane protease serine 4 (TMPRSS4).	[20]
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1 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 decreases the methylation of Transmembrane protease serine 4 (TMPRSS4).	[22]
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References

1	The upregulation of TMPRSS4, partly ascribed to the downregulation of miR?25a?p, promotes the growth of human lung adenocarcinoma via the NFB signaling pathway.Int J Oncol. 2018 Jul;53(1):148-158. doi: 10.3892/ijo.2018.4396. Epub 2018 May 7.
2	High-accuracy Detection of Preoperative Thyroid Nodules Using Combination of BRAF(V600E) Mutation and TMPRSS4 mRNA Level.Arch Med Res. 2018 Aug;49(6):365-372. doi: 10.1016/j.arcmed.2018.11.003. Epub 2018 Dec 3.
3	Targeting of TMPRSS4 sensitizes lung cancer cells to chemotherapy by impairing the proliferation machinery.Cancer Lett. 2019 Jul 1;453:21-33. doi: 10.1016/j.canlet.2019.03.013. Epub 2019 Mar 21.
4	Role of TMPRSS4 Modulation in Breast Cancer Cell Proliferation.Asian Pac J Cancer Prev. 2019 Jun 1;20(6):1849-1856. doi: 10.31557/APJCP.2019.20.6.1849.
5	Relationship between transmembrane serine protease expression and prognosis of esophageal squamous cell carcinoma.J Biol Regul Homeost Agents. 2017 Oct-Dec;31(4):1067-1072.
6	TMPRSS4 correlates with colorectal cancer pathological stage and regulates cell proliferation and self-renewal ability.Cancer Biol Ther. 2014 Mar 1;15(3):297-304. doi: 10.4161/cbt.27308. Epub 2013 Dec 12.
7	TMPRSS4 promotes invasiveness of human gastric cancer cells through activation of NF-B/MMP-9 signaling.Biomed Pharmacother. 2016 Feb;77:30-6. doi: 10.1016/j.biopha.2015.11.002. Epub 2015 Dec 11.
8	TMPRSS4 promotes cancer stem cell traits by regulating CLDN1 in hepatocellular carcinoma.Biochem Biophys Res Commun. 2017 Aug 26;490(3):906-912. doi: 10.1016/j.bbrc.2017.06.139. Epub 2017 Jun 23.
9	Cell-surface marker discovery for lung cancer.Oncotarget. 2017 Dec 7;8(69):113373-113402. doi: 10.18632/oncotarget.23009. eCollection 2017 Dec 26.
10	Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier.Oncotarget. 2016 Apr 26;7(17):23263-81. doi: 10.18632/oncotarget.8139.
11	TMPRSS4 Upregulates TWIST1 Expression through STAT3 Activation to Induce Prostate Cancer Cell Migration.Pathol Oncol Res. 2018 Apr;24(2):251-257. doi: 10.1007/s12253-017-0237-z. Epub 2017 May 2.
12	Transmembrane protease, serine 4 (TMPRSS4) is upregulated in IPF lungs and increases the fibrotic response in bleomycin-induced lung injury.PLoS One. 2018 Mar 12;13(3):e0192963. doi: 10.1371/journal.pone.0192963. eCollection 2018.
13	Vitamin D receptor expression is linked to potential markers of human thyroid papillary carcinoma.J Steroid Biochem Mol Biol. 2016 May;159:26-30. doi: 10.1016/j.jsbmb.2016.02.016. Epub 2016 Feb 22.
14	A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder. Orphanet J Rare Dis. 2013 Aug 17;8:126. doi: 10.1186/1750-1172-8-126.
15	Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and utility of TMPRSS4 as a combinatorial molecular target.Int J Oncol. 2013 Aug;43(2):416-24. doi: 10.3892/ijo.2013.1957. Epub 2013 May 24.
16	Clinical implication of TMPRSS4 expression in human gallbladder cancer.Tumour Biol. 2014 Jun;35(6):5481-6. doi: 10.1007/s13277-014-1716-4. Epub 2014 Feb 15.
17	Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
18	Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
19	Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
20	Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
21	Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
22	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.