Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3TRVL7)

• DOT Name: E3 ubiquitin-protein ligase SMURF2 (SMURF2)
• Synonyms: hSMURF2; EC 2.3.2.26; HECT-type E3 ubiquitin transferase SMURF2; SMAD ubiquitination regulatory factor 2; SMAD-specific E3 ubiquitin-protein ligase 2
• Gene Name: SMURF2
• Related Disease:
  B-cell neoplasm
  Nephropathy
  Advanced cancer
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Clear cell renal carcinoma
  Diabetic kidney disease
  Hutchinson-Gilford progeria syndrome
  Intervertebral disc degeneration
  Invasive ductal breast carcinoma
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  MASS syndrome
  Neoplasm
  Osteoarthritis
  Osteoporosis
  Pancreatic cancer
  Premature aging syndrome
  Renal cell carcinoma
  Retinoblastoma
  Squamous cell carcinoma
  Triple negative breast cancer
  Colon cancer
  Colon carcinoma
  Benign prostatic hyperplasia
  Colorectal carcinoma
  Prostate cancer
  Prostate carcinoma
  Renal fibrosis
• UniProt ID: SMUF2_HUMAN
• PDB ID: 1ZVD; 2DJY; 2JQZ; 2KXQ; 2LTZ; 6FX4; 7M3Q
• EC Number: 2.3.2.26
• Pfam ID: PF00168 ; PF00632 ; PF00397
• Sequence:
  MSNPGGRRNGPVKLRLTVLCAKNLVKKDFFRLPDPFAKVVVDGSGQCHSTDTVKNTLDPK
  WNQHYDLYIGKSDSVTISVWNHKKIHKKQGAGFLGCVRLLSNAINRLKDTGYQRLDLCKL
  GPNDNDTVRGQIVVSLQSRDRIGTGGQVVDCSRLFDNDLPDGWEERRTASGRIQYLNHIT
  RTTQWERPTRPASEYSSPGRPLSCFVDENTPISGTNGATCGQSSDPRLAERRVRSQRHRN
  YMSRTHLHTPPDLPEGYEQRTTQQGQVYFLHTQTGVSTWHDPRVPRDLSNINCEELGPLP
  PGWEIRNTATGRVYFVDHNNRTTQFTDPRLSANLHLVLNRQNQLKDQQQQQVVSLCPDDT
  ECLTVPRYKRDLVQKLKILRQELSQQQPQAGHCRIEVSREEIFEESYRQVMKMRPKDLWK
  RLMIKFRGEEGLDYGGVAREWLYLLSHEMLNPYYGLFQYSRDDIYTLQINPDSAVNPEHL
  SYFHFVGRIMGMAVFHGHYIDGGFTLPFYKQLLGKSITLDDMELVDPDLHNSLVWILEND
  ITGVLDHTFCVEHNAYGEIIQHELKPNGKSIPVNEENKKEYVRLYVNWRFLRGIEAQFLA
  LQKGFNEVIPQHLLKTFDEKELELIICGLGKIDVNDWKVNTRLKHCTPDSNIVKWFWKAV
  EFFDEERRARLLQFVTGSSRVPLQGFKALQGAAGPRLFTIHQIDACTNNLPKAHTCFNRI
  DIPPYESYEKLYEKLLTAIEETCGFAVE
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Interacts with SMAD7 to trigger SMAD7-mediated transforming growth factor beta/TGF-beta receptor ubiquitin-dependent degradation, thereby down-regulating TGF-beta signaling. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with AIMP1. Also forms a stable complex with TGF-beta receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation. SMAD2 may recruit substrates, such as SNON, for ubiquitin-dependent degradation. Negatively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation ; (Microbial infection) In case of filoviruses Ebola/EBOV and Marburg/MARV infection, the complex formed by viral matrix protein VP40 and SMURF2 facilitates virus budding.
• Tissue Specificity: Widely expressed.
• 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)
  Downregulation of SMAD2/3 (R-HSA-2173795)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Degradation of AXIN (R-HSA-4641257)
  Hedgehog 'on' state (R-HSA-5632684)
  Ub-specific processing proteases (R-HSA-5689880)
  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

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Genetic Variation	[1]
Nephropathy	DISXWP4P	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[6]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[7]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[8]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[9]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
MASS syndrome	DISI3721	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[13]
Osteoporosis	DISF2JE0	Strong	Biomarker	[12]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[14]
Premature aging syndrome	DIS51AGT	Strong	Genetic Variation	[7]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[16]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[15]
Colon cancer	DISVC52G	moderate	Biomarker	[17]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[17]
Benign prostatic hyperplasia	DISI3CW2	Limited	Altered Expression	[18]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[19]
Prostate cancer	DISF190Y	Limited	Biomarker	[18]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[18]
Renal fibrosis	DISMHI3I	Limited	Biomarker	[20]

21 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 E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[26]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[28]
Selenium	DM25CGV	Approved	Selenium decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[29]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[30]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[31]
Aspirin	DM672AH	Approved	Aspirin increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[32]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[33]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[34]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[40]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase SMURF2 (SMURF2).	[37]

References

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