Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSAEV92)

• DOT Name: Protein salvador homolog 1 (SAV1)
• Synonyms: 45 kDa WW domain protein; hWW45
• Gene Name: SAV1
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Cervicitis
  Clear cell renal carcinoma
  Congestive heart failure
  Familial adenomatous polyposis
  Hepatocellular carcinoma
  Liver cancer
  Malignant mesothelioma
  Neoplasm
  Non-alcoholic fatty liver disease
  Pancreas disorder
  Renal cell carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Neurofibromatosis type 2
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: SAV1_HUMAN
• PDB ID: 6AO5
• Pfam ID: PF00397
• Sequence:
  MLSRKKTKNEVSKPAEVQGKYVKKETSPLLRNLMPSFIRHGPTIPRRTDICLPDSSPNAF
  STSGDVVSRNQSFLRTPIQRTPHEIMRRESNRLSAPSYLARSLADVPREYGSSQSFVTEV
  SFAVENGDSGSRYYYSDNFFDGQRKRPLGDRAHEDYRYYEYNHDLFQRMPQNQGRHASGI
  GRVAATSLGNLTNHGSEDLPLPPGWSVDWTMRGRKYYIDHNTNTTHWSHPLEREGLPPGW
  ERVESSEFGTYYVDHTNKKAQYRHPCAPSVPRYDQPPPVTYQPQQTERNQSLLVPANPYH
  TAEIPDWLQVYARAPVKYDHILKWELFQLADLDTYQGMLKLLFMKELEQIVKMYEAYRQA
  LLTELENRKQRQQWYAQQHGKNF
• Function: Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which 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. 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. SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues. Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with STK3/MST2, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation.
• Tissue Specificity: Ubiquitously expressed in adult tissues with highest expression in the pancreas, aorta and interventricular septum and lowest expression in skeletal muscle. Expression was higher in fetal than in the adult heart. Expressed in various cell lines.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway: Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[1]
Cervicitis	DIS4KMW5	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[4]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[6]
Liver cancer	DISDE4BI	Strong	Altered Expression	[1]
Malignant mesothelioma	DISTHJGH	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[1]
Pancreas disorder	DISDH7NI	Strong	Genetic Variation	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[10]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Lung cancer	DISCM4YA	Limited	Altered Expression	[12]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[12]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[11]
Neurofibromatosis type 2	DISI8ECS	Limited	Biomarker	[13]
Pancreatic cancer	DISJC981	Limited	Biomarker	[11]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[11]

11 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 Protein salvador homolog 1 (SAV1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein salvador homolog 1 (SAV1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein salvador homolog 1 (SAV1).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein salvador homolog 1 (SAV1).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein salvador homolog 1 (SAV1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein salvador homolog 1 (SAV1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein salvador homolog 1 (SAV1).	[20]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Protein salvador homolog 1 (SAV1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein salvador homolog 1 (SAV1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein salvador homolog 1 (SAV1).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Protein salvador homolog 1 (SAV1).	[24]

References

• [1] Insulin receptor substrate 2: a bridge between Hippo and AKT pathways.BMB Rep. 2018 May;51(5):209-210. doi: 10.5483/bmbrep.2018.51.5.095.
• [2] Detection of torque teno midi virus/small anellovirus (TTMDV/SAV) in chronic cervicitis and cervical tumors in Isfahan, Iran.Arch Virol. 2012 Feb;157(2):291-5. doi: 10.1007/s00705-011-1169-7. Epub 2011 Nov 16.
• [3] The long noncoding RNA HOTAIR activates the Hippo pathway by directly binding to SAV1 in renal cell carcinoma.Oncotarget. 2017 Apr 25;8(35):58654-58667. doi: 10.18632/oncotarget.17414. eCollection 2017 Aug 29.
• [4] Identification of circulating placental mRNA in maternal blood of pregnancies affected with fetal congenital heart diseases at the second trimester of pregnancy: implications for early molecular screening.Prenat Diagn. 2010 Mar;30(3):229-34. doi: 10.1002/pd.2443.
• [5] -Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.Genes Dev. 2015 Jul 15;29(14):1493-506. doi: 10.1101/gad.264515.115. Epub 2015 Jul 20.
• [6] Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis.Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):E10417-E10426. doi: 10.1073/pnas.1808968115. Epub 2018 Oct 16.
• [7] YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes.Oncogene. 2012 Dec 6;31(49):5117-22. doi: 10.1038/onc.2012.5. Epub 2012 Jan 30.
• [8] SAV1, regulated by microRNA-21, suppresses tumor growth in colorectal cancer.Biochem Cell Biol. 2019 Apr;97(2):91-99. doi: 10.1139/bcb-2018-0034. Epub 2019 Jan 25.
• [9] Impact of Salmonid alphavirus infection in diploid and triploid Atlantic salmon (Salmo salar L.) fry.PLoS One. 2017 Sep 26;12(9):e0179192. doi: 10.1371/journal.pone.0179192. eCollection 2017.
• [10] Upregulation of miR-130b enhances stem cell-like phenotype in glioblastoma by inactivating the Hippo signaling pathway.Biochem Biophys Res Commun. 2015 Sep 18;465(2):194-9. doi: 10.1016/j.bbrc.2015.07.149. Epub 2015 Aug 1.
• [11] Protein salvador homolog 1 acts as a tumor suppressor and is modulated by hypermethylation in pancreatic ductal adenocarcinoma.Oncotarget. 2017 May 18;8(38):62953-62961. doi: 10.18632/oncotarget.17972. eCollection 2017 Sep 8.
• [12] WW45, a Gli1 binding protein, negatively regulated Hedgehog signaling in lung cancer.Oncotarget. 2016 Oct 18;7(42):68966-68975. doi: 10.18632/oncotarget.12155.
• [13] Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing.J Thorac Oncol. 2015 May;10(5):844-851. doi: 10.1097/JTO.0000000000000493.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.