Details of Drug Off-Target (DOT)

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

• DOT Name: Growth arrest-specific protein 6 (GAS6)
• Synonyms: GAS-6; AXL receptor tyrosine kinase ligand
• Gene Name: GAS6
• UniProt ID: GAS6_HUMAN
• PDB ID: 1H30; 2C5D; 4RA0; 5VXZ
• Pfam ID: PF12662 ; PF07645 ; PF00594 ; PF12661 ; PF00054 ; PF02210
• Sequence:
  MAPSLSPGPAALRRAPQLLLLLLAAECALAALLPAREATQFLRPRQRRAFQVFEEAKQGH
  LERECVEELCSREEAREVFENDPETDYFYPRYLDCINKYGSPYTKNSGFATCVQNLPDQC
  TPNPCDRKGTQACQDLMGNFFCLCKAGWGGRLCDKDVNECSQENGGCLQICHNKPGSFHC
  SCHSGFELSSDGRTCQDIDECADSEACGEARCKNLPGSYSCLCDEGFAYSSQEKACRDVD
  ECLQGRCEQVCVNSPGSYTCHCDGRGGLKLSQDMDTCEDILPCVPFSVAKSVKSLYLGRM
  FSGTPVIRLRFKRLQPTRLVAEFDFRTFDPEGILLFAGGHQDSTWIVLALRAGRLELQLR
  YNGVGRVTSSGPVINHGMWQTISVEELARNLVIKVNRDAVMKIAVAGDLFQPERGLYHLN
  LTVGGIPFHEKDLVQPINPRLDGCMRSWNWLNGEDTTIQETVKVNTRMQCFSVTERGSFY
  PGSGFAFYSLDYMRTPLDVGTESTWEVEVVAHIRPAADTGVLFALWAPDLRAVPLSVALV
  DYHSTKKLKKQLVVLAVEHTALALMEIKVCDGQEHVVTVSLRDGEATLEVDGTRGQSEVS
  AAQLQERLAVLERHLRSPVLTFAGGLPDVPVTSAPVTAFYRGCMTLEVNRRLLDLDEAAY
  KHSDITAHSCPPVEPAAA
• Function: Ligand for tyrosine-protein kinase receptors AXL, TYRO3 and MER whose signaling is implicated in cell growth and survival, cell adhesion and cell migration. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses; (Microbial infection) Can bridge virus envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry by apoptotic mimicry. Plays a role in Dengue cell entry by apoptotic mimicry. Plays a role in Vaccinia virus cell entry by apoptotic mimicry. Plays a role in ebolavirus and marburgvirus cell entry by apoptotic mimicry.
• Tissue Specificity: Plasma. Isoform 1 and isoform 2 are widely expressed, isoform 1 being expressed at higher levels than isoform 2 in most tissues. Isoform 2 is the predominant form in spleen.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Efferocytosis (hsa04148)
• Reactome Pathway:
  Gamma-carboxylation of protein precursors (R-HSA-159740)
  Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus (R-HSA-159763)
  Removal of aminoterminal propeptides from gamma-carboxylated proteins (R-HSA-159782)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Growth arrest-specific protein 6 (GAS6) affects the response to substance of Aspirin.	[13]
adenosine diphosphate	DMFUHKP	Investigative	Growth arrest-specific protein 6 (GAS6) increases the response to substance of adenosine diphosphate.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Growth arrest-specific protein 6 (GAS6).	[1]
Warfarin	DMJYCVW	Approved	Warfarin decreases the carboxylation of Growth arrest-specific protein 6 (GAS6).	[7]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Growth arrest-specific protein 6 (GAS6).	[2]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Growth arrest-specific protein 6 (GAS6).	[3]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Growth arrest-specific protein 6 (GAS6).	[4]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Growth arrest-specific protein 6 (GAS6).	[5]
Phosphate	DMUXQG7	Approved	Phosphate decreases the expression of Growth arrest-specific protein 6 (GAS6).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Growth arrest-specific protein 6 (GAS6).	[6]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Growth arrest-specific protein 6 (GAS6).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Growth arrest-specific protein 6 (GAS6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Growth arrest-specific protein 6 (GAS6).	[10]
Taxifolin	DMQJSF9	Preclinical	Taxifolin increases the expression of Growth arrest-specific protein 6 (GAS6).	[11]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Growth arrest-specific protein 6 (GAS6).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the degradation of Growth arrest-specific protein 6 (GAS6).	[6]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: estrogen receptor dependent or independent pathways of raloxifene. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):281-9.
• [3] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [4] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [5] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [6] Androgen receptor-dependent transactivation of growth arrest-specific gene 6 mediates inhibitory effects of testosterone on vascular calcification. J Biol Chem. 2010 Mar 5;285(10):7537-44. doi: 10.1074/jbc.M109.055087. Epub 2010 Jan 4.
• [7] Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis. Cancer Res. 2015 Sep 15;75(18):3699-705. doi: 10.1158/0008-5472.CAN-14-2887-T. Epub 2015 Jul 23.
• [8] Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. Mol Cell Biochem. 2011 Nov;357(1-2):83-94. doi: 10.1007/s11010-011-0878-2. Epub 2011 May 19.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [11] The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol Pharm Bull. 2007 Jun;30(6):1074-9.
• [12] Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis. Biochem Pharmacol. 2004 Sep 15;68(6):989-96. doi: 10.1016/j.bcp.2004.05.027.
• [13] Plasma levels of the growth arrest-specific gene 6 product (Gas6) and antiplatelet drug responsiveness in healthy subjects. J Thromb Haemost. 2006 Oct;4(10):2283-4. doi: 10.1111/j.1538-7836.2006.02155.x.
• [14] Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses. J Thromb Haemost. 2005 Apr;3(4):733-41. doi: 10.1111/j.1538-7836.2005.01186.x. Epub 2005 Feb 23.