Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5UIZR8)

• DOT Name: E3 ubiquitin-protein ligase SMURF1 (SMURF1)
• Synonyms: hSMURF1; EC 2.3.2.26; HECT-type E3 ubiquitin transferase SMURF1; SMAD ubiquitination regulatory factor 1; SMAD-specific E3 ubiquitin-protein ligase 1
• Gene Name: SMURF1
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  B-cell neoplasm
  Bone disease
  Bone Paget disease
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Epithelial ovarian cancer
  Fatty liver disease
  Frontotemporal dementia
  Gastric cancer
  Glioma
  Head-neck squamous cell carcinoma
  Hereditary chronic pancreatitis
  Latent tuberculosis infection
  Liver cancer
  Lung cancer
  Lung carcinoma
  MASS syndrome
  Neoplasm
  Non-alcoholic fatty liver disease
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic tumour
  Pick disease
  Pulmonary arterial hypertension
  Pulmonary tuberculosis
  Renal fibrosis
  Stomach cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Tuberculosis
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Cocaine addiction
  Pancreatic cancer
  Pneumocystis pneumonia
  Substance withdrawal syndrome
• UniProt ID: SMUF1_HUMAN
• PDB ID: 2LAZ; 2LB0; 2LB1; 2LTX; 3PYC
• EC Number: 2.3.2.26
• Pfam ID: PF00168 ; PF00632 ; PF00397
• Sequence:
  MSNPGTRRNGSSIKIRLTVLCAKNLAKKDFFRLPDPFAKIVVDGSGQCHSTDTVKNTLDP
  KWNQHYDLYVGKTDSITISVWNHKKIHKKQGAGFLGCVRLLSNAISRLKDTGYQRLDLCK
  LNPSDTDAVRGQIVVSLQTRDRIGTGGSVVDCRGLLENEGTVYEDSGPGRPLSCFMEEPA
  PYTDSTGAAAGGGNCRFVESPSQDQRLQAQRLRNPDVRGSLQTPQNRPHGHQSPELPEGY
  EQRTTVQGQVYFLHTQTGVSTWHDPRIPSPSGTIPGGDAAFLYEFLLQGHTSEPRDLNSV
  NCDELGPLPPGWEVRSTVSGRIYFVDHNNRTTQFTDPRLHHIMNHQCQLKEPSQPLPLPS
  EGSLEDEELPAQRYERDLVQKLKVLRHELSLQQPQAGHCRIEVSREEIFEESYRQIMKMR
  PKDLKKRLMVKFRGEEGLDYGGVAREWLYLLCHEMLNPYYGLFQYSTDNIYMLQINPDSS
  INPDHLSYFHFVGRIMGLAVFHGHYINGGFTVPFYKQLLGKPIQLSDLESVDPELHKSLV
  WILENDITPVLDHTFCVEHNAFGRILQHELKPNGRNVPVTEENKKEYVRLYVNWRFMRGI
  EAQFLALQKGFNELIPQHLLKPFDQKELELIIGGLDKIDLNDWKSNTRLKHCVADSNIVR
  WFWQAVETFDEERRARLLQFVTGSTRVPLQGFKALQGSTGAAGPRLFTIHLIDANTDNLP
  KAHTCFNRIDIPPYESYEKLYEKLLTAVEETCGFAVE
• Function: E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA. Promotes ubiquitination and subsequent proteasomal degradation of MAVS. Acts as an antagonist of TGF-beta signaling by ubiquitinating TGFBR1 and targeting it for degradation. Plays a role in dendrite formation by melanocytes.
• Tissue Specificity: Expressed in melanocytes .
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Mitophagy - animal (hsa04137)
  Endocytosis (hsa04144)
  Hedgehog sig.ling pathway (hsa04340)
  TGF-beta sig.ling pathway (hsa04350)
  Adherens junction (hsa04520)
• Reactome Pathway:
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Antigen processing (R-HSA-983168)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Bone disease	DISE1F82	Strong	Biomarker	[4]
Bone Paget disease	DISIPS4V	Strong	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[7]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[10]
Hereditary chronic pancreatitis	DISF0J1Q	Strong	Altered Expression	[11]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[12]
Liver cancer	DISDE4BI	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
MASS syndrome	DISI3721	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[7]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[15]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[16]
Pick disease	DISP6X50	Strong	Biomarker	[4]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[17]
Pulmonary tuberculosis	DIS6FLUM	Strong	Biomarker	[12]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[18]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[19]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[19]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[19]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[12]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[20]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[20]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[21]
Colon cancer	DISVC52G	moderate	Biomarker	[6]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[22]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[23]
Pancreatic cancer	DISJC981	Limited	Biomarker	[24]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[25]
Substance withdrawal syndrome	DISTT24U	Limited	Biomarker	[23]

9 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 E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[28]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[30]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[31]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[32]
Irinotecan	DMP6SC2	Approved	Irinotecan affects the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase SMURF1 (SMURF1).	[35]

References

• [1] Androgens regulate SMAD ubiquitination regulatory factor-1 expression and prostate cancer cell invasion.Prostate. 2015 May;75(6):561-72. doi: 10.1002/pros.22935. Epub 2015 Jan 28.
• [2] Deletion of SMURF 1 represses ovarian cancer invasion and EMT by modulating the DAB2IP/AKT/Skp2 feedback loop.J Cell Biochem. 2019 Jun;120(6):10643-10651. doi: 10.1002/jcb.28354. Epub 2019 Jan 22.
• [3] Knockdown of long noncoding RNA XIST mitigates the apoptosis and inflammatory injury of microglia cells after spinal cord injury through miR-27a/Smurf1 axis.Neurosci Lett. 2020 Jan 10;715:134649. doi: 10.1016/j.neulet.2019.134649. Epub 2019 Nov 25.
• [4] VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation.FASEB J. 2019 Feb;33(2):2928-2943. doi: 10.1096/fj.201801173R. Epub 2018 Oct 18.
• [5] Reciprocal regulation between TrCP and Smurf1 suppresses proliferative capacity of liver cancer cells.J Cell Physiol. 2017 Dec;232(12):3347-3359. doi: 10.1002/jcp.25780. Epub 2017 Mar 6.
• [6] MicroRNA-125a inhibits tumorigenesis by targeting Smurf1 in colorectal carcinoma.FEBS Open Bio. 2019 Jul;9(7):1305-1314. doi: 10.1002/2211-5463.12680. Epub 2019 Jun 17.
• [7] Non-proteolytic ubiquitin modification of PPAR by Smurf1 protects the liver from steatosis.PLoS Biol. 2018 Dec 19;16(12):e3000091. doi: 10.1371/journal.pbio.3000091. eCollection 2018 Dec.
• [8] miR-1254 inhibits cell proliferation, migration, and invasion by down-regulating Smurf1 in gastric cancer.Cell Death Dis. 2019 Jan 10;10(1):32. doi: 10.1038/s41419-018-1262-x.
• [9] Suppression of the Smurf1 Expression Inhibits Tumor Progression in Gliomas.Cell Mol Neurobiol. 2018 Mar;38(2):421-430. doi: 10.1007/s10571-017-0485-1. Epub 2017 Mar 20.
• [10] SMURF1 silencing diminishes a CD44-high cancer stem cell-like population in head and neck squamous cell carcinoma.Mol Cancer. 2014 Dec 3;13:260. doi: 10.1186/1476-4598-13-260.
• [11] Upregulation of microRNA?94?p inhibits hypopharyngeal carcinoma cell proliferation, migration and invasion by targeting SMURF1 via the mTOR signaling pathway.Int J Oncol. 2019 Apr;54(4):1245-1255. doi: 10.3892/ijo.2019.4711. Epub 2019 Feb 4.
• [12] The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense.Cell Host Microbe. 2017 Jan 11;21(1):59-72. doi: 10.1016/j.chom.2016.11.002. Epub 2016 Dec 22.
• [13] Smurf1 regulates lung cancer cell growth and migration through interaction with and ubiquitination of PIPKI.Oncogene. 2017 Oct 12;36(41):5668-5680. doi: 10.1038/onc.2017.166. Epub 2017 Jun 5.
• [14] SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts.Nat Commun. 2017 Feb 20;8:14570. doi: 10.1038/ncomms14570.
• [15] Selective compounds enhance osteoblastic activity by targeting HECT domain of ubiquitin ligase Smurf1.Oncotarget. 2016 Jul 18;8(31):50521-50533. doi: 10.18632/oncotarget.10648. eCollection 2017 Aug 1.
• [16] Identification of SMURF1 as a possible target for 7q21.3-22.1 amplification detected in a pancreatic cancer cell line by in-house array-based comparative genomic hybridization.Cancer Sci. 2008 May;99(5):986-94. doi: 10.1111/j.1349-7006.2008.00779.x.
• [17] MicroRNA-424(322) as a new marker of disease progression in pulmonary arterial hypertension and its role in right ventricular hypertrophy by targeting SMURF1.Cardiovasc Res. 2018 Jan 1;114(1):53-64. doi: 10.1093/cvr/cvx187.
• [18] Connexin32 ameliorates renal fibrosis in diabetic mice by promoting K48-linked NADPH oxidase 4 polyubiquitination and degradation.Br J Pharmacol. 2020 Jan;177(1):145-160. doi: 10.1111/bph.14853. Epub 2019 Dec 23.
• [19] miR-4319 inhibited the development of thyroid cancer by modulating FUS-stabilized SMURF1.J Cell Biochem. 2020 Jan;121(1):174-182. doi: 10.1002/jcb.29026. Epub 2019 May 30.
• [20] USF2 inhibits the transcriptional activity of Smurf1 and Smurf2 to promote breast cancer tumorigenesis.Cell Signal. 2019 Jan;53:49-58. doi: 10.1016/j.cellsig.2018.09.013. Epub 2018 Sep 21.
• [21] Ubiquitin ligase SMURF1 functions as a prognostic marker and promotes growth and metastasis of clear cell renal cell carcinoma.FEBS Open Bio. 2017 Feb 23;7(4):577-586. doi: 10.1002/2211-5463.12204. eCollection 2017 Apr.
• [22] Ubiquitination of UVRAG by SMURF1 promotes autophagosome maturation and inhibits hepatocellular carcinoma growth.Autophagy. 2019 Jul;15(7):1130-1149. doi: 10.1080/15548627.2019.1570063. Epub 2019 Jan 27.
• [23] E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking.Biol Psychiatry. 2018 Dec 15;84(12):881-892. doi: 10.1016/j.biopsych.2018.07.013. Epub 2018 Jul 21.
• [24] SMURF1 amplification promotes invasiveness in pancreatic cancer.PLoS One. 2011;6(8):e23924. doi: 10.1371/journal.pone.0023924. Epub 2011 Aug 22.
• [25] The E3 ubiquitin ligase SMURF1 regulates cell-fate specification and outflow tract septation during mammalian heart development.Sci Rep. 2018 Jun 22;8(1):9542. doi: 10.1038/s41598-018-27854-8.
• [26] 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.
• [27] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [28] 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.
• [29] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [30] 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.
• [31] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [32] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [33] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [34] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [35] 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.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.