Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSCAL0V)

• DOT Name: Integrin alpha-4 (ITGA4)
• Synonyms: CD49 antigen-like family member D; Integrin alpha-IV; VLA-4 subunit alpha; CD antigen CD49d
• Gene Name: ITGA4
• UniProt ID: ITA4_HUMAN
• PDB ID: 3V4P; 3V4V; 4HKC; 5C7Z; 5FPI
• Pfam ID: PF01839 ; PF08441 ; PF20805 ; PF20806
• Sequence:
  MAWEARREPGPRRAAVRETVMLLLCLGVPTGRPYNVDTESALLYQGPHNTLFGYSVVLHS
  HGANRWLLVGAPTANWLANASVINPGAIYRCRIGKNPGQTCEQLQLGSPNGEPCGKTCLE
  ERDNQWLGVTLSRQPGENGSIVTCGHRWKNIFYIKNENKLPTGGCYGVPPDLRTELSKRI
  APCYQDYVKKFGENFASCQAGISSFYTKDLIVMGAPGSSYWTGSLFVYNITTNKYKAFLD
  KQNQVKFGSYLGYSVGAGHFRSQHTTEVVGGAPQHEQIGKAYIFSIDEKELNILHEMKGK
  KLGSYFGASVCAVDLNADGFSDLLVGAPMQSTIREEGRVFVYINSGSGAVMNAMETNLVG
  SDKYAARFGESIVNLGDIDNDGFEDVAIGAPQEDDLQGAIYIYNGRADGISSTFSQRIEG
  LQISKSLSMFGQSISGQIDADNNGYVDVAVGAFRSDSAVLLRTRPVVIVDASLSHPESVN
  RTKFDCVENGWPSVCIDLTLCFSYKGKEVPGYIVLFYNMSLDVNRKAESPPRFYFSSNGT
  SDVITGSIQVSSREANCRTHQAFMRKDVRDILTPIQIEAAYHLGPHVISKRSTEEFPPLQ
  PILQQKKEKDIMKKTINFARFCAHENCSADLQVSAKIGFLKPHENKTYLAVGSMKTLMLN
  VSLFNAGDDAYETTLHVKLPVGLYFIKILELEEKQINCEVTDNSGVVQLDCSIGYIYVDH
  LSRIDISFLLDVSSLSRAEEDLSITVHATCENEEEMDNLKHSRVTVAIPLKYEVKLTVHG
  FVNPTSFVYGSNDENEPETCMVEKMNLTFHVINTGNSMAPNVSVEIMVPNSFSPQTDKLF
  NILDVQTTTGECHFENYQRVCALEQQKSAMQTLKGIVRFLSKTDKRLLYCIKADPHCLNF
  LCNFGKMESGKEASVHIQLEGRPSILEMDETSALKFEIRATGFPEPNPRVIELNKDENVA
  HVLLEGLHHQRPKRYFTIVIISSSLLLGLIVLLLISYVMWKAGFFKRQYKSILQEENRRD
  SWSYINSKSNDD
• Function: Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha-4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGA4:ITGB1 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. Integrin ITGA4:ITGB1 represses PRKCA-mediated L-type voltage-gated channel Ca(2+) influx and ROCK-mediated calcium sensitivity in vascular smooth muscle cells via its interaction with SVEP1, thereby inhibiting vasocontraction.
• Tissue Specificity: Expressed in vascular smooth muscle cells (at protein level).
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (hsa04514)
  Hematopoietic cell lineage (hsa04640)
  Leukocyte transendothelial migration (hsa04670)
  Intesti.l immune network for IgA production (hsa04672)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Human papillomavirus infection (hsa05165)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Integrin cell surface interactions (R-HSA-216083)
  RUNX3 Regulates Immune Response and Cell Migration (R-HSA-8949275)
  Potential therapeutics for SARS (R-HSA-9679191)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

28 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 alpha-4 (ITGA4).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integrin alpha-4 (ITGA4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Integrin alpha-4 (ITGA4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrin alpha-4 (ITGA4).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Integrin alpha-4 (ITGA4).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Integrin alpha-4 (ITGA4).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Integrin alpha-4 (ITGA4).	[7]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Integrin alpha-4 (ITGA4).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Integrin alpha-4 (ITGA4).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Integrin alpha-4 (ITGA4).	[2]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Integrin alpha-4 (ITGA4).	[2]
Cimetidine	DMH61ZB	Approved	Cimetidine decreases the expression of Integrin alpha-4 (ITGA4).	[10]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Integrin alpha-4 (ITGA4).	[11]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Integrin alpha-4 (ITGA4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Integrin alpha-4 (ITGA4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Integrin alpha-4 (ITGA4).	[15]
Tesmilifene	DMPB36I	Discontinued in Phase 2	Tesmilifene decreases the expression of Integrin alpha-4 (ITGA4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Integrin alpha-4 (ITGA4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Integrin alpha-4 (ITGA4).	[9]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Integrin alpha-4 (ITGA4).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Integrin alpha-4 (ITGA4).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Integrin alpha-4 (ITGA4).	[21]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Integrin alpha-4 (ITGA4).	[20]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Integrin alpha-4 (ITGA4).	[2]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Integrin alpha-4 (ITGA4).	[22]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Integrin alpha-4 (ITGA4).	[23]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Integrin alpha-4 (ITGA4).	[20]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Integrin alpha-4 (ITGA4).	[23]

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 increases the methylation of Integrin alpha-4 (ITGA4).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Integrin alpha-4 (ITGA4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Integrin alpha-4 (ITGA4).	[17]

References

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