Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWXCF3)

• DOT Name: Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A)
• Synonyms: IgG Fc receptor III-A; CD16-II; CD16a antigen; Fc-gamma RIII-alpha; Fc-gamma RIII; Fc-gamma RIIIa; FcRIII; FcRIIIa; FcgammaRIIIA; FcR-10; IgG Fc receptor III-2; CD antigen CD16a
• Gene Name: FCGR3A
• Related Disease: Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity
• UniProt ID: FCG3A_HUMAN
• PDB ID: 3AY4; 3SGJ; 3SGK; 3WN5; 5BW7; 5D6D; 5ML9; 5MN2; 5VU0; 5XJE; 5XJF; 5YC5; 7SEG; 7URU
• Pfam ID: PF13895
• Sequence:
  MWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQW
  FHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKE
  EDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLFGSKN
  VSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDW
  KDHKFKWRKDPQDK
• Function: Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Optimally activated upon binding of clustered antigen-IgG complexes displayed on cell surfaces, triggers lysis of antibody-coated cells, a process known as antibody-dependent cellular cytotoxicity (ADCC). Does not bind free monomeric IgG, thus avoiding inappropriate effector cell activation in the absence of antigenic trigger. Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC. Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis. Fc-binding subunit that associates with CD247 and/or FCER1G adapters to form functional signaling complexes. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation. Costimulates NK cells and trigger lysis of target cells independently of IgG binding. Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells. Mediates enhanced ADCC in response to afucosylated IgGs ; (Microbial infection) Involved in Dengue virus pathogenesis via antibody-dependent enhancement (ADE) mechanism. Secondary infection with Dengue virus triggers elevated levels of afucosylated non-neutralizing IgG1s with reactivity to viral envelope/E protein. Viral antigen-IgG1 complexes bind with high affinity to FCGR3A, facilitating virus entry in myeloid cells and subsequent viral replication.
• Tissue Specificity: Expressed in natural killer cells (at protein level) . Expressed in a subset of circulating monocytes (at protein level) .
• KEGG Pathway:
  Phagosome (hsa04145)
  Osteoclast differentiation (hsa04380)
  Neutrophil extracellular trap formation (hsa04613)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leishmaniasis (hsa05140)
  Staphylococcus aureus infection (hsa05150)
  Tuberculosis (hsa05152)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  FCGR activation (R-HSA-2029481)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity	DIS0J4KF	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cetuximab	DMLNCE0	Approved	Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A) increases the response of Cetuximab.	[11]
Rituximab	DM1YVZT	Approved	Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A) increases the response of Rituximab.	[12]
Infliximab	DMH7OIA	Phase 2 Trial	Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A) increases the ACR20 response ADR of Infliximab.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[10]

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 Low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A).	[8]

References

• [1] Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J Clin Invest. 2012 Oct;122(10):3769-80. doi: 10.1172/JCI64837. Epub 2012 Sep 24.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [4] Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance. Hematology. 2007 Dec;12(6):511-7. doi: 10.1080/10245330701562535.
• [5] 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.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [10] Effect of bisphenol A on human neutrophils immunophenotype. Sci Rep. 2020 Feb 20;10(1):3083. doi: 10.1038/s41598-020-59753-2.
• [11] FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007 Aug 20;25(24):3712-8. doi: 10.1200/JCO.2006.08.8021.
• [12] FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood. 2006 Oct 15;108(8):2720-5. doi: 10.1182/blood-2006-01-009480. Epub 2006 Apr 11.
• [13] Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis. 2009 Oct;68(10):1547-52. doi: 10.1136/ard.2008.096982. Epub 2008 Oct 17.