Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40S1SJ)

• DOT Name: TGF-beta receptor type-1 (TGFBR1)
• Synonyms: TGFR-1; EC 2.7.11.30; Activin A receptor type II-like protein kinase of 53kD; Activin receptor-like kinase 5; ALK-5; ALK5; Serine/threonine-protein kinase receptor R4; SKR4; TGF-beta type I receptor; Transforming growth factor-beta receptor type I; TGF-beta receptor type I; TbetaR-I
• Gene Name: TGFBR1
• Related Disease:
  Familial thoracic aortic aneurysm and aortic dissection
  Loeys-Dietz syndrome
  Loeys-Dietz syndrome 1
  Multiple self-healing squamous epithelioma
• UniProt ID: TGFR1_HUMAN
• PDB ID: 1B6C ; 1IAS ; 1PY5 ; 1RW8 ; 1VJY ; 2L5S ; 2PJY ; 2WOT ; 2WOU ; 2X7O ; 3FAA ; 3GXL ; 3HMM ; 3KCF ; 3KFD ; 3TZM ; 4X0M ; 4X2F ; 4X2G ; 4X2J ; 4X2K ; 4X2N ; 5E8S ; 5E8T ; 5E8U ; 5E8W ; 5E8X ; 5E8Z ; 5E90 ; 5FRI ; 5QIK ; 5QIL ; 5QIM ; 5QTZ ; 5QU0 ; 5USQ ; 6B8Y ; 6MAC
• EC Number: 2.7.11.30
• Pfam ID: PF01064 ; PF00069 ; PF08515
• Sequence:
  MEAAVAAPRPRLLLLVLAAAAAAAAALLPGATALQCFCHLCTKDNFTCVTDGLCFVSVTE
  TTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPG
  LGPVELAAVIAGPVCFVCISLMLMVYICHNRTVIHHRVPNEEDPSLDRPFISEGTTLKDL
  IYDMTTSGSGSGLPLLVQRTIARTIVLQESIGKGRFGEVWRGKWRGEEVAVKIFSSREER
  SWFREAEIYQTVMLRHENILGFIAADNKDNGTWTQLWLVSDYHEHGSLFDYLNRYTVTVE
  GMIKLALSTASGLAHLHMEIVGTQGKPAIAHRDLKSKNILVKKNGTCCIADLGLAVRHDS
  ATDTIDIAPNHRVGTKRYMAPEVLDDSINMKHFESFKRADIYAMGLVFWEIARRCSIGGI
  HEDYQLPYYDLVPSDPSVEEMRKVVCEQKLRPNIPNRWQSCEALRVMAKIMRECWYANGA
  ARLTALRIKKTLSQLSQQEGIKM
• Function: Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.
• Tissue Specificity: Found in all tissues examined, most abundant in placenta and least abundant in brain and heart. Expressed in a variety of cancer cell lines .
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Cytokine-cytokine receptor interaction (hsa04060)
  FoxO sig.ling pathway (hsa04068)
  Endocytosis (hsa04144)
  Cellular senescence (hsa04218)
  TGF-beta sig.ling pathway (hsa04350)
  Apelin sig.ling pathway (hsa04371)
  Osteoclast differentiation (hsa04380)
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Th17 cell differentiation (hsa04659)
  Relaxin sig.ling pathway (hsa04926)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Chagas disease (hsa05142)
  Hepatitis B (hsa05161)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Pancreatic cancer (hsa05212)
  Chronic myeloid leukemia (hsa05220)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)
  SMAD2/3 Phosphorylation Motif Mutants in Cancer (R-HSA-3304356)
  TGFBR2 Kinase Domain Mutants in Cancer (R-HSA-3645790)
  TGFBR1 KD Mutants in Cancer (R-HSA-3656532)
  TGFBR1 LBD Mutants in Cancer (R-HSA-3656535)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Definitive	Autosomal dominant	[1]
Loeys-Dietz syndrome	DIS4FUPZ	Definitive	Autosomal dominant	[1]
Loeys-Dietz syndrome 1	DISD43VO	Definitive	Autosomal dominant	[2]
Multiple self-healing squamous epithelioma	DISPYT7K	Definitive	Autosomal dominant	[1]

32 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 TGF-beta receptor type-1 (TGFBR1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of TGF-beta receptor type-1 (TGFBR1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of TGF-beta receptor type-1 (TGFBR1).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[11]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[12]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of TGF-beta receptor type-1 (TGFBR1).	[13]
Vitamin A	DMJ2AH4	Approved	Vitamin A decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[14]
Glucosamine	DM4ZLFD	Approved	Glucosamine increases the expression of TGF-beta receptor type-1 (TGFBR1).	[15]
Ketamine	DMT5HA4	Approved	Ketamine increases the expression of TGF-beta receptor type-1 (TGFBR1).	[16]
Diazepam	DM08E9O	Approved	Diazepam increases the expression of TGF-beta receptor type-1 (TGFBR1).	[17]
Lenalidomide	DM6Q7U4	Approved	Lenalidomide decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of TGF-beta receptor type-1 (TGFBR1).	[18]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[19]
Glycyrrhizin	DM8M2N3	Phase 3	Glycyrrhizin decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[20]
GEA-6414	DM8J0MK	Phase 1/2	GEA-6414 decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TGF-beta receptor type-1 (TGFBR1).	[24]
Acteoside	DM0YHKB	Terminated	Acteoside decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TGF-beta receptor type-1 (TGFBR1).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TGF-beta receptor type-1 (TGFBR1).	[28]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of TGF-beta receptor type-1 (TGFBR1).	[30]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[31]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of TGF-beta receptor type-1 (TGFBR1).	[32]
Manganese	DMKT129	Investigative	Manganese decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[33]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of TGF-beta receptor type-1 (TGFBR1).	[34]
Galangin	DM5TQ2O	Investigative	Galangin increases the expression of TGF-beta receptor type-1 (TGFBR1).	[35]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal decreases the expression of TGF-beta receptor type-1 (TGFBR1).	[36]
Oxalic Acid	DMLN2GQ	Investigative	Oxalic Acid increases the expression of TGF-beta receptor type-1 (TGFBR1).	[37]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PIPERINE	DMYEAB1	Phase 1/2	PIPERINE affects the binding of TGF-beta receptor type-1 (TGFBR1).	[21]
PMID28870136-Compound-49	DMTUC9E	Patented	PMID28870136-Compound-49 affects the binding of TGF-beta receptor type-1 (TGFBR1).	[25]

3 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 TGF-beta receptor type-1 (TGFBR1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of TGF-beta receptor type-1 (TGFBR1).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane affects the methylation of TGF-beta receptor type-1 (TGFBR1).	[29]

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