Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWCK1K6)

• DOT Name: Integrin beta-3 (ITGB3)
• Synonyms: Platelet membrane glycoprotein IIIa; GPIIIa; CD antigen CD61
• Gene Name: ITGB3
• Related Disease:
  Glanzmann thrombasthenia
  Bleeding disorder, platelet-type, 24
  Glanzmann thrombasthenia 2
  Platelet-type bleeding disorder 16
  Autosomal dominant macrothrombocytopenia
  Obsolete Glanzmann's thrombasthenia
• UniProt ID: ITB3_HUMAN
• PDB ID: 1JV2 ; 1KUP ; 1KUZ ; 1L5G ; 1M1X ; 1M8O ; 1MIZ ; 1MK7 ; 1MK9 ; 1S4X ; 1TYE ; 1U8C ; 2K9J ; 2KNC ; 2KV9 ; 2L1C ; 2L91 ; 2LJD ; 2LJE ; 2LJF ; 2MTP ; 2N9Y ; 2Q6W ; 2RMZ ; 2RN0 ; 2VC2 ; 2VDK ; 2VDL ; 2VDM ; 2VDN ; 2VDO ; 2VDP ; 2VDQ ; 2VDR ; 3FCS ; 3FCU ; 3IJE ; 3NID ; 3NIF ; 3NIG ; 3T3M ; 3T3P ; 3ZDX ; 3ZDY ; 3ZDZ ; 3ZE0 ; 3ZE1 ; 3ZE2 ; 4CAK ; 4G1E ; 4G1M ; 4MMX ; 4MMY ; 4MMZ ; 4O02 ; 4Z7N ; 4Z7O ; 4Z7Q ; 5HDB ; 6AVQ ; 6AVR ; 6AVU ; 6BXB ; 6BXF ; 6BXJ ; 6CKB ; 6MK0 ; 6MSL ; 6MSU ; 6NAJ ; 6V4P ; 7KN0 ; 7L8P ; 7LA4 ; 7TCT ; 7TD8 ; 7THO ; 7TMZ ; 7TPD ; 7U60 ; 7U9F ; 7U9V ; 7UBR ; 7UCY ; 7UDG ; 7UDH ; 7UE0 ; 7UFH ; 7UH8 ; 7UJE ; 7UJK ; 7UK9 ; 7UKO ; 7UKP ; 7UKT ; 8T2U ; 8T2V
• Pfam ID: PF07974 ; PF18372 ; PF08725 ; PF07965 ; PF00362 ; PF17205
• Sequence:
  MRARPRPRPLWATVLALGALAGVGVGGPNICTTRGVSSCQQCLAVSPMCAWCSDEALPLG
  SPRCDLKENLLKDNCAPESIEFPVSEARVLEDRPLSDKGSGDSSQVTQVSPQRIALRLRP
  DDSKNFSIQVRQVEDYPVDIYYLMDLSYSMKDDLWSIQNLGTKLATQMRKLTSNLRIGFG
  AFVDKPVSPYMYISPPEALENPCYDMKTTCLPMFGYKHVLTLTDQVTRFNEEVKKQSVSR
  NRDAPEGGFDAIMQATVCDEKIGWRNDASHLLVFTTDAKTHIALDGRLAGIVQPNDGQCH
  VGSDNHYSASTTMDYPSLGLMTEKLSQKNINLIFAVTENVVNLYQNYSELIPGTTVGVLS
  MDSSNVLQLIVDAYGKIRSKVELEVRDLPEELSLSFNATCLNNEVIPGLKSCMGLKIGDT
  VSFSIEAKVRGCPQEKEKSFTIKPVGFKDSLIVQVTFDCDCACQAQAEPNSHRCNNGNGT
  FECGVCRCGPGWLGSQCECSEEDYRPSQQDECSPREGQPVCSQRGECLCGQCVCHSSDFG
  KITGKYCECDDFSCVRYKGEMCSGHGQCSCGDCLCDSDWTGYYCNCTTRTDTCMSSNGLL
  CSGRGKCECGSCVCIQPGSYGDTCEKCPTCPDACTFKKECVECKKFDRGALHDENTCNRY
  CRDEIESVKELKDTGKDAVNCTYKNEDDCVVRFQYYEDSSGKSILYVVEEPECPKGPDIL
  VVLLSVMGAILLIGLAALLIWKLLITIHDRKEFAKFEEERARAKWDTANNPLYKEATSTF
  TNITYRGT
• Function: Integrin alpha-V/beta-3 (ITGAV:ITGB3) is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 (ITGA2B:ITGB3) is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial surface. Fibrinogen binding enhances SELP expression in activated platelets. ITGAV:ITGB3 binds to fractalkine (CX3CL1) and acts as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling. ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling. ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling. ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling. ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling. ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling. ITGAV:ITGB3 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1. ITGAV:ITGB3 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1. In brain, plays a role in synaptic transmission and plasticity. Involved in the regulation of the serotonin neurotransmission, is required to localize to specific compartments within the synapse the serotonin receptor SLC6A4 and for an appropriate reuptake of serotonin. Controls excitatory synaptic strength by regulating GRIA2-containing AMPAR endocytosis, which affects AMPAR abundance and composition. ITGAV:ITGB3 act as a receptor for CD40LG. ITGAV:ITGB3 acts as a receptor for IBSP and promotes cell adhesion and migration to IBSP ; (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Herpes virus 8/HHV-8; (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Coxsackievirus A9; (Microbial infection) Acts as a receptor for Hantaan virus; (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Cytomegalovirus/HHV-5; (Microbial infection) Integrin ITGA5:ITGB3 acts as a receptor for Human metapneumovirus; (Microbial infection) Integrin ITGAV:ITGB3 acts aP05556s a receptor for Human parechovirus 1; (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for West nile virus; (Microbial infection) In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
• Tissue Specificity: Isoform beta-3A and isoform beta-3C are widely expressed. Isoform beta-3A is specifically expressed in osteoblast cells; isoform beta-3C is specifically expressed in prostate and testis.
• KEGG Pathway:
  Virion - Herpesvirus (hsa03266)
  Rap1 sig.ling pathway (hsa04015)
  Phagosome (hsa04145)
  Efferocytosis (hsa04148)
  PI3K-Akt sig.ling pathway (hsa04151)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  Hematopoietic cell lineage (hsa04640)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Thyroid hormone sig.ling pathway (hsa04919)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Herpes simplex virus 1 infection (hsa05168)
  Proteoglycans in cancer (hsa05205)
  MicroR.s in cancer (hsa05206)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Elastic fibre formation (R-HSA-1566948)
  PECAM1 interactions (R-HSA-210990)
  Molecules associated with elastic fibres (R-HSA-2129379)
  Integrin cell surface interactions (R-HSA-216083)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Syndecan interactions (R-HSA-3000170)
  ECM proteoglycans (R-HSA-3000178)
  Integrin signaling (R-HSA-354192)
  GRB2 (R-HSA-354194)
  p130Cas linkage to MAPK signaling for integrins (R-HSA-372708)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Signal transduction by L1 (R-HSA-445144)
  MAP2K and MAPK activation (R-HSA-5674135)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glanzmann thrombasthenia	DISFGGTG	Definitive	Autosomal recessive	[1]
Bleeding disorder, platelet-type, 24	DISUF258	Strong	Autosomal dominant	[2]
Glanzmann thrombasthenia 2	DISR66KM	Strong	Autosomal recessive	[3]
Platelet-type bleeding disorder 16	DISPUR84	Moderate	Autosomal dominant	[1]
Autosomal dominant macrothrombocytopenia	DISUTMSW	Supportive	Autosomal dominant	[4]
Obsolete Glanzmann's thrombasthenia	DISFH7MK	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Integrin beta-3 (ITGB3) decreases the response to substance of Aspirin.	[30]
Etoposide	DMNH3PG	Approved	Integrin beta-3 (ITGB3) increases the response to substance of Etoposide.	[15]
DTI-015	DMXZRW0	Approved	Integrin beta-3 (ITGB3) increases the response to substance of DTI-015.	[15]
Clopidogrel	DMOL54H	Approved	Integrin beta-3 (ITGB3) decreases the response to substance of Clopidogrel.	[31]
Eptifibatide	DMQXTJS	Approved	Integrin beta-3 (ITGB3) increases the Surgical and medical procedures ADR of Eptifibatide.	[32]
Abciximab	DMJO6GV	Approved	Integrin beta-3 (ITGB3) increases the Surgical and medical procedures ADR of Abciximab.	[32]
Tirofiban	DMQG17S	Approved	Integrin beta-3 (ITGB3) increases the Surgical and medical procedures ADR of Tirofiban.	[32]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Serotonin	DMOFCRY	Investigative	Integrin beta-3 (ITGB3) affects the abundance of Serotonin.	[33]

25 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 Integrin beta-3 (ITGB3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Integrin beta-3 (ITGB3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Integrin beta-3 (ITGB3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Integrin beta-3 (ITGB3).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Integrin beta-3 (ITGB3).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Integrin beta-3 (ITGB3).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Integrin beta-3 (ITGB3).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Integrin beta-3 (ITGB3).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Integrin beta-3 (ITGB3).	[12]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Integrin beta-3 (ITGB3).	[13]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Integrin beta-3 (ITGB3).	[14]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Integrin beta-3 (ITGB3).	[15]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the expression of Integrin beta-3 (ITGB3).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Integrin beta-3 (ITGB3).	[18]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Integrin beta-3 (ITGB3).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Integrin beta-3 (ITGB3).	[21]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Integrin beta-3 (ITGB3).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrin beta-3 (ITGB3).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Integrin beta-3 (ITGB3).	[5]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Integrin beta-3 (ITGB3).	[24]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Integrin beta-3 (ITGB3).	[25]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of Integrin beta-3 (ITGB3).	[26]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone affects the expression of Integrin beta-3 (ITGB3).	[27]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of Integrin beta-3 (ITGB3).	[28]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of Integrin beta-3 (ITGB3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Integrin beta-3 (ITGB3).	[17]

1 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 increases the methylation of Integrin beta-3 (ITGB3).	[20]

References

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