Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS78EC3)

• DOT Name: Transcriptional coactivator YAP1
• Synonyms: Yes-associated protein 1; Protein yorkie homolog; Yes-associated protein YAP65 homolog
• Gene Name: YAP1
• Related Disease: Uveal coloboma-cleft lip and palate-intellectual disability
• UniProt ID: YAP1_HUMAN
• PDB ID: 1JMQ ; 1K5R ; 1K9Q ; 1K9R ; 2LAW ; 2LAX ; 2LAY ; 2LTV ; 2LTW ; 3KYS ; 3MHR ; 4RE1 ; 4REX ; 5OAQ ; 5YDX ; 5YDY ; 6G6X ; 6G8I ; 6G8J ; 6G8K ; 6G8L ; 6G8P ; 6G8Q ; 6GE3 ; 6GE4 ; 6GE5 ; 6GE6 ; 6GEC ; 6GEE ; 6GEG ; 6GEI ; 6GEK ; 6HIK ; 6HIL ; 6Q2X ; 7O07 ; 8A8Q ; 8A8R
• Pfam ID: PF00397
• Sequence:
  MDPGQQPPPQPAPQGQGQPPSQPPQGQGPPSGPGQPAPAATQAAPQAPPAGHQIVHVRGD
  SETDLEALFNAVMNPKTANVPQTVPMRLRKLPDSFFKPPEPKSHSRQASTDAGTAGALTP
  QHVRAHSSPASLQLGAVSPGTLTPTGVVSGPAATPTAQHLRQSSFEIPDDVPLPAGWEMA
  KTSSGQRYFLNHIDQTTTWQDPRKAMLSQMNVTAPTSPPVQQNMMNSASGPLPDGWEQAM
  TQDGEIYYINHKNKTTSWLDPRLDPRFAMNQRISQSAPVKQPPPLAPQSPQGGVMGGSNS
  NQQQQMRLQQLQMEKERLRLKQQELLRQAMRNINPSTANSPKCQELALRSQLPTLEQDGG
  TQNPVSSPGMSQELRTMTTNSSDPFLNSGTYHSRDESTDSGLSMSSYSVPRTPDDFLNSV
  DEMDTGDTINQSTLPSQQNRFPDYLEAIPGTNVDLGTLEGDGMNIEGEELMPSLQEALSS
  DILNDMESVLAATKLDKESFLTWL
• Function: Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization. Plays a key role in controlling cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction. Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1. In conjunction with WWTR1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation; [Isoform 2]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3); [Isoform 3]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3).
• Tissue Specificity: Increased expression seen in some liver and prostate cancers. Isoforms lacking the transactivation domain found in striatal neurons of patients with Huntington disease (at protein level).
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway:
  Signaling by Hippo (R-HSA-2028269)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)
  RUNX3 regulates YAP1-mediated transcription (R-HSA-8951671)
  EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)
  Formation of axial mesoderm (R-HSA-9796292)
  Zygotic genome activation (ZGA) (R-HSA-9819196)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Uveal coloboma-cleft lip and palate-intellectual disability	DIS132JP	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Transcriptional coactivator YAP1 affects the response to substance of Gemcitabine.	[28]
Sorafenib	DMS8IFC	Approved	Transcriptional coactivator YAP1 decreases the response to substance of Sorafenib.	[29]
Vemurafenib	DM62UG5	Approved	Transcriptional coactivator YAP1 decreases the response to substance of Vemurafenib.	[30]

20 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 Transcriptional coactivator YAP1.	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcriptional coactivator YAP1.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional coactivator YAP1.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcriptional coactivator YAP1.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transcriptional coactivator YAP1.	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Transcriptional coactivator YAP1.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcriptional coactivator YAP1.	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transcriptional coactivator YAP1.	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcriptional coactivator YAP1.	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcriptional coactivator YAP1.	[12]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Transcriptional coactivator YAP1.	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcriptional coactivator YAP1.	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcriptional coactivator YAP1.	[17]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Transcriptional coactivator YAP1.	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcriptional coactivator YAP1.	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcriptional coactivator YAP1.	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transcriptional coactivator YAP1.	[22]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the expression of Transcriptional coactivator YAP1.	[24]
LICOAGROCHACONE A	DMWY0TN	Investigative	LICOAGROCHACONE A decreases the expression of Transcriptional coactivator YAP1.	[25]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 decreases the expression of Transcriptional coactivator YAP1.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the localization of Transcriptional coactivator YAP1.	[9]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the localization of Transcriptional coactivator YAP1.	[23]
Oleic acid	DM54O1Z	Investigative	Oleic acid affects the localization of Transcriptional coactivator YAP1.	[23]
gingerol	DMNXYSM	Investigative	gingerol affects the localization of Transcriptional coactivator YAP1.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Transcriptional coactivator YAP1.	[13]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the phosphorylation of Transcriptional coactivator YAP1.	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcriptional coactivator YAP1.	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Transcriptional coactivator YAP1.	[18]

References

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