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Targets Associated with Immuno Processes - Cellular signalling
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Targets Associated to Immuno Processes
Full documentation can be found in the GtoImmuPdb immuno cell type data documentation (PDF). ✖ |
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| GPCRs | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| ADGRE2 (Adhesion Class GPCRs) |
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ADGRE2 is included in GtoImmuPdb because its tissue expression profile and its ability to activate secretion of inflammatory cytokines (IL-8, TNF) by monocytes and macrophages [262] ... | ||
| ADGRG3 (Adhesion Class GPCRs) |
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ADGRG3 is expressed by immune cells. It is required for proper B cell development in the spleen [667] ... | ||
| A2A receptor (Adenosine receptors) |
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Agonist stimulation of the A2A and A3 receptors down-regulates production of the pro-inflammatory mediators TNF-α and IL-8 in human synoviocytes [654] ... | ||
| A2B receptor (Adenosine receptors) |
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A2B receptor is discussed in this immuno-oncology review [3] ... | ||
| C3a receptor (Complement peptide receptors) |
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Complement C3a receptor 1 is the receptor for complement factor C3a, a component of the alternative complement cascade. It can have pro-inflammatory actions, but can also counteract the proinflammatory effects of C5a. The complement system plays a critical role intestinal immune homeostasis. In particular, C3 and the C3aR have been identified as being involved in regulating the intestinal immune response during chronic colitis [621,680] ... |
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| C5a1 receptor (Complement peptide receptors) |
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C5aR is typically associated with the compement cascade and innate immunity. MorphoSys have an anti-C5aR monoclonal antibody (MOR210; TJ210) in preclinical development as an immuno-oncology agent. The goal of anti-C5aR therapy is to reduce the effects that activation of the C5a/C5aR axis has on promoting cancer cell migration and invasiveness [259,382,448-449] ... |
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| C5a2 receptor (Complement peptide receptors) |
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C5aR is typically associated with the compement cascade and innate immunity. However, the complement C5a receptor 2 may act as a decoy receptor for C5a, as it has no reported G protein signalling capacity. | ||
| CB1 receptor (Cannabinoid receptors) |
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CB1 receptor is involved in controlling mast cell degranulation and maturation [613] ... | ||
| CB2 receptor (Cannabinoid receptors) |
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CB2 receptor on eosinophils mainly mediates anti-inflammatory and immunomodulatory actions e.g. downregulation of pro-inflammatory mediator release. Pharmacological targeting with the CB2 receptor selective antagonist SR144528 attenuates the recruitment of eosinophils and ear swelling in a murine chronic contact dermatitis model [464] ... | ||
| CCR2 (Chemokine receptors) |
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CCR2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CCR2 is discussed in relation to immuno-oncology in [3] ... | ||
| CCR6 (Chemokine receptors) |
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CCR6 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. CCR6 is expressed on a variety of immune cells including memory and regulatory T-cells [323,363] ... | ||
| CCR7 (Chemokine receptors) |
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CCR7 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. | ||
| CCR9 (Chemokine receptors) |
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CCR9 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. Activation of CCR9 by CCL25 plays a key role in leukocyte recruitment to the gut and CCR9 antagonists are being pursued as therapeutic agents for inflammatory bowel disease [681] ... | ||
| chemerin receptor 1 (Chemerin receptors) |
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Studies in CMKLR1 (chemerin receptor 1) knockout mice highlight the role of this receptor in inflammation and obesity. Chemerin receptor 1 is activated by the lipid-derived, anti-inflammatory autacoid ligand resolvin E1. As its name suggests, reslovin E1 is involved in resolving physiological inflammatory responses. The metabolically stable resolvin E1 analogue, RX-10045 (navamepent) has completed Phase 2 clinical trials in several occular inflammation indications. In relation to multiple sclerosis (MS), clinical EAE is significantly reduced in CMKLR1 KO mice. Taking this in to consideration with data that confirm CMKLR1 expression by the main effector cells in MS, this protein is judged to be a novel and tractable target for therapeutic intervention in MS. CMKLR1 antagonists are being pursued as anti-inflammatory agents. The selective CMKLR1 antagonist CCX832 was developed by ChemoCentryx and GlaxoSmithKline as a potential anti-psoriatic medication, but development appears to have halted at Phase 1. |
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| CXCR2 (Chemokine receptors) |
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CXCR2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CXCR2 is discussed in relation to immuno-oncology in [3] ... | ||
| CXCR5 (Chemokine receptors) |
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CXCR5 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. | ||
| CX3CR1 (Chemokine receptors) |
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CX3CR1 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. | ||
| DP1 receptor (Prostanoid receptors) |
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DP1 receptor activation by prostaglandins mediates chemotaxis of pro-inflammatory cells such as basophils, eosinophils, and T cells. DP2 and DP1 may function to counteract each other's inflammatory action [249] ... | ||
| EP4 receptor (Prostanoid receptors) |
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The EP4 prostanoid receptor is one of four receptor subtypes for prostaglandin PGE2. The anti- and pro-inflammatory (and non-inflammatory) activities of this receptor are reviewed in [716] ... | ||
| FFA2 receptor (Free fatty acid receptors) |
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FFAR2 is a GPCR activated by short-chain fatty acids, and evidence suggests that FFAR2 (and FFAR3) mediate beneficial effects associated with a fiber-rich diet. These GPCRs are of interest as targets for the treatment of inflammatory and metabolic diseases. FFAR2 is included in GtoImmuPdb as it is highly expressed on immune cells, in particular neutrophils, and evidence points to a role in diseases with dysfunctional neutrophil responses, such as inflammatory bowel disease (IBD). A Phase 2 trial of the clinical candidate GLPG0974 in ulcerative colitis has been completed (see NCT0182932). In vitro and in vivo studies suggest that the short-chain fatty acid/FFAR2 axis is modulated by metabolites of cholera toxin, that are produced by gut microbiota, which leads to enhanced mucosal antibody responses against enteric pathogen infection [707] ... |
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| FPR1 (Formylpeptide receptors) |
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The primary function of FPR1 is recognition of formylpeptides. Detection of bacterial N-formylpeptides via FPR1 activates immune-cell chemotaxis and cytokine release, making this GPCR an important component of the host defense mechanism. Osei-Owusu et al. (2019) demonstrated that FPR1 on immune cells is the target of the needle cap protein (LcrV; Uniprot accession P0C7U7) of Yersinia pestis (the plague bacterium), via which the bacteria destroy host immune cells [472] ... |
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| FPR2 (Formylpeptide receptors, Leukotriene receptors) |
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Formyl peptide receptor type 2 (FPR2/ALX) activation by lipoxin A4 and annexin 1 has been linked to resolution of inflammation, via upregulation of anti-inflammatory cytokines including IL-10. Resolvin D1-mediated activation of FPR2/ALX appears to resolve salivary gland inflammation in a mouse model of Sjögren syndrome [663] ... | ||
| GPR183 (Class A Orphans with emerging pharmacology) |
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Gpr183-deficient mice show a reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre [312,492] ... | ||
| MRGPRX2 (Class A Orphans with emerging pharmacology) |
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Expression of MRGPRX2 was initially reported predominantly in sensory neurons of the dorsal root ganglion. More recently expression has been detected in human mast cells. In these cells the receptor is activated by the antimicrobial peptide LL-37, resulting in calcium mobilisation and degranulation [412,611] ... | ||
| NK1 receptor (Tachykinin receptors) |
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Expression in monocytes, macrophages and T helper cells suggests a role in inflammation/immunity. | ||
| PAF receptor (Platelet-activating factor receptor) |
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PAF deficiency results in defective inflammatory response to infection in mice. | ||
| PAR2 (Proteinase-activated receptors) |
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PAR2 receptors have been reported to elicit pain and inflammation through a neurogenic mechanism of action, causing release of substance P, activation of NK1 receptors, and sensitization of TRPV1 voltage-gated ion channels. This action can be negated using a selective NK1 receptor antagonist (L732,138) or a TRPV1 receptor antagonist (capsazepine) [206] ... | ||
| succinate receptor (Succinate receptor) |
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Succinate acts an an alarmin that triggers the initiation and propagation of danger signals resulting from tissue injury or inflammatory stimuli. It acts through the succinate receptor, SUCNR1. SUCNR1-expressing macrophages release succinate that acts in an autocrine and paracrine feed-forward loop that elevates SUCNR1 expression and leads to enhanced IL-1β production [367] ... | ||
| Ion Channels | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| KCa3.1 (Calcium- and sodium-activated potassium channels (KCa, KNa)) |
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KCa3.1 and KV1.3 are the predominant potassium channels involved in regulating the hyperpolarized (negative) membrane potential which is critical for immune cell activation [156,185,406] ... | ||
| P2X7 (P2X receptors) |
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The P2X7 receptor is involved in NLRP3-type inflammasome formation, and subsequent maturation of IL-1β [366,520] ... | ||
| TRPV1 (Transient Receptor Potential channels (TRP)) |
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Several lines of evidence suggest that TRPV1 is implicated in some inflammatory processes [24,57,378,385,550] ... | ||
| Nuclear Hormone Receptors | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| Farnesoid X receptor (1H. Liver X receptor-like receptors) |
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FXR is predominantly expressed in liver, intestine, kidney and adipose tissue, but has also been detected in immune cells (CD4+, CD8+, CD19+ and CD14+ cells) [557] ... | ||
| Liver X receptor-α (1H. Liver X receptor-like receptors) |
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Liver X receptors (LXR) are involved in the regulation of lipid metabolism and inflammatory responses. As such they are novel drug targets for cholesterol homeostasis (hypercholesterolaemia), inflammation, and with potential therapeutic effects in neurodegenerative diseases [700] ... | ||
| RAR-related orphan receptor-γ (1F. Retinoic acid-related orphans) |
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RORγ is a nuclear receptor transcription factor that acts as an immune cell master control switch (most likely associated with expression of the RORγt isoform). This receptor is an essential regulator of type 17 effector T cell differentiation and function. RORγt inhibitors (antagonists and inverse agonists) [143,209,451,590] ... | ||
| Enzymes | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| 3-phosphoinositide dependent protein kinase 1 (PDK1 family) |
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In addition to its role in oncology, in mouse studies, PDK1 is reported to play a part in regulating insulin sensitivity (and inhibiting adipose tissue inflammation), via the Pdk1/Foxo1 pathway and expression of Ccr2 [309] ... | ||
| ABL proto-oncogene 1, non-receptor tyrosine kinase (Abl family) |
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Included in GtoImmuPdb based on its association with leukemia. | ||
| aconitate decarboxylase 1 (Itaconate biosynthesis) |
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Itaconate (itaconic acid) is generated from the citric acid (TCA) cycle intermediate cis-aconitic acid which is produced by mitochondria. Itaconate is synthesised by the enzyme aconitate decarboxylase 1 (referred to as immunoresponsive gene 1 or IRG1). Its synthesis links metabolism to immunity and it plays an important role in the macrophage-based immune response [130,165] ... | ||
| ADAM10 (M12: Astacin/Adamalysin) |
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ADAM10 has been identified as the primary physiologically relevant sheddase responsible for cleavage of |
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| ADAM17 (M12: Astacin/Adamalysin) |
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The proteolytic activity of ADAM17 (a type I transmembrane metalloproteinase; a.k.a.TNF-alpha converting enzyme or TACE) is involved in the shedding of the extracellular domains of several transmembrane proteins e.g. cytokines (TNFα), growth factors, receptors (IL-6R and TNF-R for example) and adhesion molecules. Cleavage of substrates, including TNFα, IL-6R and L-selectin, produce pro-inflammatory effects stimulating both innate and acquired immune responses. ADAM17 activity is crucial during development (ADAM17 knockout is embryonic lethal), and it has been shown that the soluble IL-6R/IL-6 complex generates agonist-like signals in a process termed IL-6 trans-signaling. The generation and maintenance of several inflammatory and autoimmune diseases is driven by IL-6 trans-signaling [103] ... | ||
| ADAM8 (M12: Astacin/Adamalysin) |
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ADAM8 is reported to drive acute allergen-induced airway inflammation in a mouse model, and effect negated by ADAM8-deficiency (antibody-induced or gene knockout) [488] ... | ||
| Adenosine deaminase (Adenosine turnover) |
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Adenosine deaminase deficiency causes immunodeficiency (ADA deficiency or ADA-SCID). Around 30 known genotypes are associated with this autosomal recessive metabolic disorder. Mitotically active cells such as developing T cells and B cells are susceptible to this deficiency, expaining the resulting ... | ||
| Arginase I (Arginase) |
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The role of ARG1 in immuno-oncology is reviewed in [3] ... | ||
| Arginase II (Arginase) |
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The role of ARG2 in immuno-oncology is reviewed in [3] ... | ||
| BLK proto-oncogene, Src family tyrosine kinase (Src family) |
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BLK is a B cell-specific kinase. In Blk knockout mice B cells develop normally and show unaltered in vitro activation and humoral immune responses to T cell-dependent and -independent antigens, a result which is indicative of functional redundancy of Blk in B cell development and immune responses [626] ... | ||
| BMX non-receptor tyrosine kinase (Tec family) |
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The TEC family protein tyrosine kinases have been identified as key components of T-cell-receptor activation and signalling. TEC family kinases are expressed predominantly by haematopoietic cells. T cells express ITK, TXK and TEC [53] ... | ||
| B-Raf proto-oncogene, serine/threonine kinase (RAF family) |
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BRAFV600E- immuno-oncology [3] ... | ||
| Bruton tyrosine kinase (Tec family) |
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The TEC family protein tyrosine kinases have been identified as key components of T-cell-receptor activation and signalling. TEC family kinases are expressed predominantly by haematopoietic cells. T cells express ITK, TXK and TEC [53] ... | ||
| calcium/calmodulin dependent protein kinase IV (CAMK1 family) |
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CAMKIV has been implicated in the differentiation of Th17 cells, suggesting CAMKIV as a target for therapeutic intervention in Th17-driven autoimmune diseases [325] ... | ||
| Caspase 1 (C14: Caspase) |
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Caspase 1 is also known as interleukin-1beta (IL-1α) converting enzyme (ICE). Amongst its substrates are the precursors of the inflammatory cytokines IL-1β and IL-18, which it proteolytically cleaves into active mature peptides. | ||
| Caspase 3 (C14: Caspase) |
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Defective caspase 3 expression in immune effector cells may influence susceptibility to Kawasaki disease, an acute vasculitis syndrome affecting small- and medium-sized arteries of infants and children [469] ... | ||
| Caspase 8 (C14: Caspase) |
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Roles of apoptotic caspases extending beyond cell death, for example, mediating cellular immune processes such as inflammasome modulation, necroptosis and pro-inflammatory cytokine processing have been reported [389] ... | ||
| cathepsin C (C1: Papain) |
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Cathepsin C (CatC) is a lysosomal cysteine protease that is constitutively expressed at high levels in lung, kidney, liver and spleen. As well as activity in lysosomal protein degradation, cathepsin C also plays a key role in the activation of granule serine proteases in cytotoxic T cells, natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase, proteinase 3). Dysregulated activation of neutrophil elastase at inflammatory sites induces the release of pro-inflammatoy mediators and can lead to acute tissue injury. This mechanism is recognised as causing lung damage in neutrophil driven conditions such as asthma and COPD, and has driven the pharmaceutical industry to search for cathepsin C inhibitors with clinical utility (e.g. brensocatib; formerly AZD7986 and INS1007). SARS-CoV-2 and COVID-19: CatC has been proposed as a drug target to combat ARDS-associated inflammatory lung damage in patients with severe COVID-19. In this setting CatC inhibitors would be expected to protect the lungs from ARDS by reducing the observed virally-induced hyperinflammation that leads to diffuse alveolar collapse and pulmonary tissue damage [330] ... |
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| cathepsin G (S1: Chymotrypsin) |
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Cathepsin G is a leukocyte serine protease of the chymotrypsin family, related to neutrophil elastase and the granzymes. It is stored in azurophil granules and acts intracellularly to degrade ingested host pathogens and axtracellularly to breakdown ECM components at sites of inflammation. Cathepsin ... | ||
| cathepsin H (C1: Papain) |
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Cathepsin H may act as a pro-granzyme B convertase [141] ... | ||
| cathepsin L (C1: Papain) |
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Cathepsins B, H and L have become important therapeutic targets as their proteolytic activity has been implicated in several pathological inflammatory conditions, such as arthritis and periodontitis. Therefore, pharmacological inhibitors of these enzymes are in development as novel therapeutics. | ||
| cathepsin S (C1: Papain) |
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Cathepsin S is expressed in the lysosome of antigen presenting cells (dendritic cells, B-cells and macrophages) where it processes the invariant chain-MHC-II complex (a chaperone protein that prevents premature peptide loading) inside antigen presenting cells and in this way controls antigen presentation. Due to this role in antigen presentation, inhibition of cathepsin S is expected to cause immunosuppression [629] ... | ||
| Cbl proto-oncogene B (E3 ubiquitin ligase components) |
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Cbl-b is an E3 ubiquitin ligase that is involved in regulating T cell activation and peripheral T cell tolerance [359,370] ... | ||
| cereblon (E3 ubiquitin ligase components) |
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Cereblon is a direct molecular target for the immunomodulatory and antiproliferative activities of |
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| component of inhibitor of nuclear factor kappa B kinase complex (IKK family) |
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Ikkα is one of the catalytic subunits of the IκB kinase (IKK) complex, an upstream component of the NF-κB signal transduction cascade; NF-κB signaling being involved in propagating the cellular response to inflammation. IKK frees NF-κB from its inhibitory interaction with IκBα (inhibitor of kappa B), allowing NF-κB translocation to the nucleus where it modulates transcriptional activity. Additional functions of Ikkα beyond NF-κB activation are reviewed in [261] ... | ||
| C-terminal Src kinase (Csk family) |
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CSK is an inhibitory regulator of Src family kinases, a family of protein tyrosine kinases indispensable to the initiation of signal transduction via ITAM-bearing immunoreceptors, and cytokine, growth factor, and pattern recognition receptor signalling. CSK phosphorylates an inhibitory tyrosine residue at the C terminus of Src kinases, leading to autoinhibition. CSK-induced Src kinase inhibition can also be mediated by binding to PEST family receptor tyrosine phosphatases [655] ... | ||
| CTP synthase 1 (Nucleotide turnover) |
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CTPS1 is critical for the proliferation of lymphoid cells [399] ... | ||
| cyclic GMP-AMP synthase (Cyclic GMP-AMP turnover) |
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Cyclic GMP-AMP synthase (cGAS) directly binds to cytosolic DNA, and in response catalyses the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Thus cGAS acts as a sensor of DNA in the cytoplasm, which is an indicator of pathogen invasion [617] ... | ||
| cyclin dependent kinase 6 (CDK4 subfamily) |
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Phenotypic abnormalities in CDK6 knockout mice suggest biological roles in addition to mitotic cell cycle regulation. Alternate roles include involvement in hematopoietic function and inhibition of T cell differentiation [224,485] ... | ||
| diacylglycerol kinase zeta (Diacylglycerol kinases) |
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Highly expressed in T cells compared to other hematopoietic cells; negative regulator of T cell activation [737] ... | ||
| enhancer of zeste 2 polycomb repressive complex 2 subunit (2.1.1.43 Histone methyltransferases (HMTs)) |
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EZH2 is involved in hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis, with notable participation in regulating the differentiation and function of T cells. This role suggests potential applications in immune-mediated conditions, including autoimmune disorders [636] ... | ||
| eukaryotic translation initiation factor 2 alpha kinase 2 (Other PEK family kinases) |
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Protein kinase-R (EIF2AK2) is activated by virally-introduced double-stranded RNA (dsRNA), and is therefore involved in protection against viral infection. Protein activator of the interferon-induced protein kinase EIF2AK2 (PACT; PRKRA) also activates protein kinase-R. Activated protein kinase-R phosphorylates the eukaryotic translation initiation factor eIF2α inhibiting viral protein synthesis [205] ... | ||
| eukaryotic translation initiation factor 2 alpha kinase 4 (GCN2 subfamily) |
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GCN2 is a so-called 'stress kinase'. It phosphorylates serine 51 on the global transcription factor eIF2α upon activation by uncharged tRNA; tRNAs accumulate when amino acid levels are depleted. Phospho-eIF2α blocks translation to cause proliferative arrest. GCN2 plays several roles in the immune system. It is required for dendritic cell activation and antigen presentation. The GCN2 stress response is required for both optimal proliferation of CD8+ T cells after antigen stimulation, and trafficking to lymphoid organs, i.e. for normal cytotoxic T cell function [644] ... |
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| F-box protein 3 (E3 ubiquitin ligase components) |
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F-box protein 3 is involved in pathways that regulate pro-inflammatory cytokine release, and is a molecular target for anti-inflammatory drug development. | ||
| FER tyrosine kinase (Fer family) |
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FER acts downstream of the activated high affinity immunoglobulin epsilon receptor (FCεR1) and plays a role in FCεR1-mediated signaling in mast cells, regulation of mast cell degranulation, leukocyte recruitment, and leukocyte extravasation following bacterial lipopolysaccharide (LPS ... | ||
| FGR proto-oncogene, Src family tyrosine kinase (Src family) |
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Fgr may be involved in neutrophil migration, potentially via binding to intergrins [45] ... | ||
| FKBP prolyl isomerase 1A (Peptidyl-prolyl cis/trans isomerases) |
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| FYN proto-oncogene, Src family tyrosine kinase (Src family) |
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Animal models and cell line studies indicate a critical role for Fyn in proximal T-cell antigen receptor (TCR) signal transduction [477] ... | ||
| glycogen synthase kinase 3 beta (GSK subfamily) |
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GSK3β plays an essential function in T cell differentiation and proliferation, and its activity is inhibited following antigen-driven T cell activation [62-63,376,463] ... | ||
| HCK proto-oncogene, Src family tyrosine kinase (Src family) |
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Hck is thought to be involved in neutrophil migration, potentially via binding to intergrins [45] ... | ||
| histone deacetylase 3 (3.5.1.- Histone deacetylases (HDACs)) |
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A 2017 study reports that HDAC3 (more so than HDACs -6, -1/2, or -8) regulates inflammatory gene expression in rheumatoid arthritis fibroblast-like synoviocytes, and is required for type I IFN production [19] ... | ||
| histone deacetylase 6 (3.5.1.- Histone deacetylases (HDACs)) |
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Accumulating evidence indicates that non-selective HDAC inhibitors exhibit immunosuppressive/anti-inflammatory activity in vitro and in vivo, and have potential as a drug class with uses in immune and inflammatory diseases [46,183,525,541,574] ... | ||
| IL2 inducible T cell kinase (Tec family) |
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The TEC family protein tyrosine kinases have been identified as key components of T-cell-receptor activation and signalling. TEC family kinases are expressed predominantly by haematopoietic cells. T cells express ITK, TXK and TEC [53] ... | ||
| indoleamine 2,3-dioxygenase 1 (1.13.11.- Dioxygenases) |
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The indoleamine 2,3 dioxygenase (IDO) branch of the kynurenine (KYN) pathway of tryptophan metabolism has been intensely studied in relation to immune tolerance and allergy. IDO is generally considered to be a tolerogenic, immunosuppressive enzyme, that is induced by IFN-γ. It provides a negative feedback pathway that limits uncontrolled immune responses. Its immunosuppressive actions arise from its promotion of tryptophan depletion, and elevation of KYN metabolite levels. The aryl hydrocarbon receptor serves as a receptor for KYN and should be considered when evaluating the IDO-KYN pathway in immune homeostasis and its potential to modulate innate and adaptive immune responses [324] ... | ||
| Inducible NOS (Nitric oxide synthases) |
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The role of iNOS in immuno-oncology is reviewed in [3] ... | ||
| inhibitor of nuclear factor kappa B kinase subunit beta (IKK family) |
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Iκβ kinase β (IKK-2) is the pivotal enzyme component of the Iκβ kinase (IKK) complex, a complex crucial in regulating expression and activation of inflammatory mediators in airway epithelium. IKK-2 is an attractive target for development of pharmaceutical inhibitors with antiinflammatory action as treatments for asthma and chronic obstructive pulmonary disease (COPD) [49,68,586] ... | ||
| INPP5D (Inositol polyphosphate phosphatases) |
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SHIP1 activators are proposed as novel anti-inflammatory agents e.g. rosiptor (AQX-1125) which is in Phase 2 and 3 clinical trials [447,606] ... | ||
| interleukin 1 receptor associated kinase 1 (Interleukin-1 receptor-associated kinase (IRAK) family) |
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One of the two proximal mediators of IL-1 signaling via the IL-1 receptor, plays a part in IL-1-induced upregulation of the transcription factor NF-κB, the other being IRAK2. Interacts with other proteins including TRAF6, Myd88, CHUK, IKK2 and TLR4. | ||
| interleukin 1 receptor associated kinase 2 (Interleukin-1 receptor-associated kinase (IRAK) family) |
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IRAK2 is one of the proximal mediators of IL-1 signalling via the IL-1 receptor, the other being IRAK1. It plays a part in IL-1-induced upregulation of the transcription factor NF-κB. IRAK2 interacts with TRAF6 and Myd88. | ||
| interleukin 1 receptor associated kinase 3 (Interleukin-1 receptor-associated kinase (IRAK) family) |
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IRAK3 expression is restricted to monocytes and macrophages. | ||
| interleukin 1 receptor associated kinase 4 (Interleukin-1 receptor-associated kinase (IRAK) family) |
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IRAK4 is essential for most innate immune responses to bacteria and viruses, and IRAK4 deficiency (caused by mutations) has been shown to result in recurrent invasive pneumococcal disease [414] ... | ||
| IP3 kinase B (Inositol 1,4,5-trisphosphate 3-kinases) |
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IP3 kinase B (ITPKB) as an essential mediator of T cell activation, whose inhibition is considered a novel approach to treat autoimmune disease [419] ... | ||
| Janus kinase 1 (Janus kinase (JakA) family) |
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The JAK1 tyrosine kinase is crucial for signaling of certain type I and type II cytokines, via receptors belonging to the IL-2, IL-4 and IL-6 receptor families as well as neurotrophin-1 and leptin receptors (all type I cytokine receptors). JAK1 is also involved in signalling via type I ... | ||
| Janus kinase 2 (Janus kinase (JakA) family) |
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JAK2 signal transduction is a critical mediator of the immune response and is implicated in autoimmune conditions and in graft-versus-host disease (GvHD). The pro-inflammatory effects of IL-6, IL-12, and IL-23 on T cells are mediated via JAK2 [59,61,601] ... | ||
| Janus kinase 3 (Janus kinase (JakA) family) |
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Psoriatic skin samples show elevated JAK3 (and JAK1) expression, with signalling predominantly through STAT3 [15] ... | ||
| large tumor suppressor kinase 1 (NDR family) |
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LATS1 and LATS2 are included in the GToImmuPdb because of their crucial role in Hipo signalling, a major mammalian signalling cascade that has recently been identified as playing an important role in shaping the innate immune response [1-2,4]. | ||
| large tumor suppressor kinase 2 (NDR family) |
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LATS1 and LATS2 are included in the GToImmuPdb because of their crucial role in Hipo signalling, a major mammalian signalling cascade that has recently been identified as playing an important role in shaping the innate immune response [1-2,4]. | ||
| LCK proto-oncogene, Src family tyrosine kinase (Src family) |
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Phosphorylation and activation of Lck is an early and critical step in pre-TCR (T cell receptor) and TCR signalling. Activated Lck phosphorylates immunoreceptor tyrosine-based activation motifs of the ζ chain of the TCR leading to recruitment and activation of ZAP-70 tyrosine kinase, and activation of downstream MAPKs and NF-κB. TCR-based signals are required at several stages of T-cell development and it is thought that Lck is the major contributor to TCR signal transduction (with the related Src tyrosine kinase Fyn also playing a role) [477] ... | ||
| LYN proto-oncogene, Src family tyrosine kinase (Src family) |
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LYN is a Src family tyrosine kinase, expressed predominantly in hematopoietic cells, but also in neural, liver, and adipose tissues. LYN appears to function as a rheostat to modulate B cell signaling, and can be activating or inhibitory in action, depending on the B cell receptor and interacting protein complement present in particular cells [193,203,635] ... | ||
| mitogen-activated protein kinase 1 (ERK subfamily) |
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In endothelial cells of the vasculature, and in activated human mast cells, ERK serves as an anti-inflammatory signal that suppresses production of pro-inflammatory mediators [317,383] ... | ||
| mitogen-activated protein kinase 8 (JNK subfamily) |
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By regulating AP-1 transcriptional activity in response to cytokine activation, JNK1 contributes to the production of immunomodulators such as RANTES, IL-8 and GM-CSF . | ||
| mitogen-activated protein kinase 9 (JNK subfamily) |
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Experimental evidence suggests that JNK2 is important in T-cell differentiation [283,545,610,704] ... | ||
| mitogen-activated protein kinase kinase kinase 7 (TAK1 subfamily) |
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TAK1 (MAP3K7) mediates signaling downstream of multiple cytokine receptors and is functionally important in mitogen, immune, and inflammatory signaling pathways [144,548] ... | ||
| mitogen-activated protein kinase kinase kinase 8 (STE-unique family) |
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MAP3K8 (a.k.a. TPL2) is the primary regulator of ERK-mediated gene transcription downstream of multiple proinflammatory stimuli [202,698] ... | ||
| MMP14 (M10: Matrix metallopeptidase) |
|
MMP14 is included in GtoImmuPdb based on its contribution to degradation of collagenous cartilage matrix in rheumatoid arthritis. An anti-MMP14 antibody, DX-2400 [159] ... | ||
| MMP8 (M10: Matrix metallopeptidase) |
|
MMP8 is included in GtoImmuPdb based on its potential protective role in asthma. | ||
| NIMA related kinase 7 (NIMA (never in mitosis gene a)- related kinase (NEK) family) |
|
NEK7 is a component of the NLRP3 inflammasome. It is activated by deglutathionylation by glutathione transferase omega 1-1 (GSTO1-1), and this in turn promotes NLRP3 inflammasome-mediated maturation of the proinflammatory cytokines IL-1β amd IL-18 [266] ... | ||
| otulin (C101: OTULIN peptidase) |
|
Otulin is reported as a negative regulator of inflammation and autoimmunity [146] ... | ||
| p21 (RAC1) activated kinase 1 (PAKA subfamily) |
|
PAK1 is reported to modulate a pro-inflammatory PPARγ/NF-κB cascade in intestinal inflammation, that may be relevant in inflammatory bowel disease and colitis-associated cancer [147] ... | ||
| p21 (RAC1) activated kinase 2 (PAKA subfamily) |
|
Pharmacological inhibition of PAK2 has immunosuppressive effects [459] ... | ||
| peptidylprolyl isomerase A (Peptidyl-prolyl cis/trans isomerases) |
|
Cyclophilin A (CypA) is well known as a specific binding protein for cyclosporin A (CsA) [233] ... | ||
| phosphatase and tensin homolog (Lipid phosphate phosphatases) |
|
Accumulating evidence suggests that loss-of-function mutations or deletion of PTEN is an immune evasion mechanism exploited by tumour cells [602] ... | ||
| phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (Phosphatidylinositol-4,5-bisphosphate 3-kinase family, Phosphatidylinositol kinases) |
|
PI3Kα is primarily recognised for its oncogenic function. We have included it in GtoImmuPdb based on its numerous GO immune process associations. | ||
| phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (Phosphatidylinositol-4,5-bisphosphate 3-kinase family, Phosphatidylinositol kinases) |
|
PI3Kδ is preferentially expressed in cells of hemopoietic lineage and is involved in neutrophil chemotaxis. It is the only PI3K isoform with expression restricted to leukocytes. Genetic and pharmacological inactivation of PI3Kδ indicates its importantance for the function of T cells, B cell, mast cells and neutrophils. PI3kδ is a promising target for drugs for preventing or treating inflammation, autoimmunity and transplant rejection [238] ... | ||
| phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (Phosphatidylinositol-4,5-bisphosphate 3-kinase family, Phosphatidylinositol kinases) |
|
The role of PI3Kγ in immuno-oncology is reviewed in [3] ... | ||
| phosphodiesterase 4B (Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)) |
|
PDE4 is a drug target, whose inhibition has anti-inflammatory action. PDE4 inhibitors have already entered clinical use, being employed in the treatment of inflammatory skin conditions such as psoriatic arthritis ( |
||
| phosphodiesterase 4D (Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)) |
|
The selective PDE4 inhibitor |
||
| phosphodiesterase 5A (Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)) |
|
The role of PDE5A in immuno-oncology is reviewed in [3] ... | ||
| phosphoinositide-3-kinase regulatory subunit 1 (Phosphatidylinositol kinases) |
|
p85α is included in GtoImmuPdb as it is the regulatory subunit of several PI3Ks (e.g. PI3Kδ and PI3Kγ) with roles in leukocyte biology and therefore important for immunity [380] ... | ||
| PLCγ1 (Phosphoinositide-specific phospholipase C) |
|
Two structurally similar isoforms of PLCγ are expressed by mast cells (PLCγ1 and PLCγ2). Both are important enzymes in the integrated signalling pathways leading to mast cell activation [214,547] ... | ||
| PLCγ2 (Phosphoinositide-specific phospholipase C) |
|
Two structurally similar isoforms of PLCγ are expressed by mast cells (PLCγ1 and PLCγ2). Both are important enzymes in the integrated signalling pathways leading to mast cell activation [214,547] ... | ||
| protein kinase C beta (Alpha subfamily) |
|
PKCβ is included in GtoImmuPdb based on its GO immune process associations. | ||
| protein kinase C delta (Delta subfamily) |
|
PKCδ is included in GtoImmuPdb based on its GO immune process associations. | ||
| protein kinase C epsilon (Eta subfamily) |
|
PKCε is included in GtoImmuPdb based on its GO immune process associations. | ||
| protein kinase C eta (Eta subfamily) |
|
PKCη is included in GtoImmuPdb based on the involvement of other PKC isozymes in immune processes. | ||
| protein kinase C gamma (Alpha subfamily) |
|
PKCγ is included in GtoImmuPdb based on the involvement of other PKC isozymes in immune processes. | ||
| protein kinase C theta (Delta subfamily) |
|
PKC-θ is a novel subfamily PKC found predominantly in hematopoietic cells [32] ... | ||
| protein kinase C zeta (Iota subfamily) |
|
PKCζ is included in GtoImmuPdb based on its GO process associations. | ||
| protein kinase, DNA-activated, catalytic subunit (Other PIKK family kinases) |
|
Protein kinase, DNA-activated, catalytic polypeptide (DNA-PKcs) principally acts to repair DNA in a process called non-homologous end joining (NHEJ). NHEJ is required for V(D)J recombination (somatic recombination) in developing lymphocytes during the early stages of T and B cell maturation. DNA-PKc ... | ||
| protein kinase N1 (Protein kinase N (PKN) family) |
|
Evidence suggests that PKN1 plays a role in modulation of the NF-κB signalling pathway. Specifically, in Salmonella infection, PKN1 is hijacked by a bacterial effector protein which results in inhibition of NF-κB-dependent gene expression (i.e. inhibition of production of the proinflammatory cytokines that would normally effect bacterial destruction and removal) [237] ... | ||
| protein tyrosine kinase 2 (Fak family) |
|
FAK and Pyk2 are phosphorylated downstream of the T cell antigen receptor (TCR) to bring about receptor-specific T cell development and activation [109] ... | ||
| protein tyrosine kinase 2 beta (Fak family) |
|
FAK and Pyk2 are phosphorylated downstream of the T cell antigen receptor (TCR) to bring about receptor-specific (e.g. chemokine and integrin receptors) T cell development and activation [109] ... | ||
| protein tyrosine phosphatase non-receptor type 11 (Protein tyrosine phosphatases non-receptor type (PTPN)) |
|
SHP2 regulates programmed cell death 1 (PD-1)-mediated signal transduction and it is therefore involved in immune checkpoint modulation. | ||
| protein tyrosine phosphatase non-receptor type 2 (Protein tyrosine phosphatases non-receptor type (PTPN)) |
|
Inhibition of PTPN1/2 promotes T cell-mediated anti-tumour immunity [48,361,744] ... | ||
| protein tyrosine phosphatase non-receptor type 22 (Protein tyrosine phosphatases non-receptor type (PTPN)) |
|
PTPN22 is a lymphoid-specific, inducible protein tyrosine phosphatase [127] ... | ||
| RAB27A, member RAS oncogene family (RAB subfamily) |
|
Small molecule inhibitors of Rab27a-JFC1 binding, termed Nexinhibs (neutrophil exocytosis inhibitors) demonstrate the druggability of Rab GTPases and inhibition of exocytosis of azurophilic granules in human neutrophils without affecting other important innate immune responses, including phagocytosis and neutrophil extracellular trap production. These thus have potential use as an inhibitor of systemic inflammation [295] ... | ||
| receptor interacting serine/threonine kinase 2 (Receptor interacting protein kinase (RIPK) family) |
|
RIPK2 is involved in innate immune responses, mediating pro-inflammatory signaling from the bacterial peptidoglycan-sensing NOD1/NOD2 subfamily of innate immune pattern recognition receptors (PRRs) and signalling downstream from the Toll-like receptor (TLR) family of PRRs. Further evidence suggesting an inflammatory role is the targeting of RIPK2 (along with RIPK1/3) by the IAP family E3 ubiquitin ligases (enzymes playing a critical role in innate immunity) [457] ... | ||
| receptor interacting serine/threonine kinase 3 (Receptor interacting protein kinase (RIPK) family) |
|
RIPK1 and RIPK3 are involved in necroptosis and as such are critical regulators of inflammation and cell death [444,529,578,660] ... | ||
| serine/threonine kinase 11 (LKB subfamily) |
|
Development of fatal TH2-dominant inflammatory symptoms in mice with a specific Stk11 knockout in their Treg cells, and experiments showing Stk11's role in the coordination of metabolic and functional fitness of Treg cells, suggest that this kinase acts as a crucial checkpoint that actively maintains Treg cell survival and homeostatic function [240,706] ... | ||
| sirtuin 1 (3.5.1.- Histone deacetylases (HDACs)) |
|
Sirtuin 1 has been suggested as a molecular target for host-directed therapy against Mycobacterium tuberculosis infection by research that shows that activation of sirtuin 1 decreases lung pathology, reduces inflammation, and enhances drug efficacy against Mycobacterium tuberculosis [118] ... | ||
| sphingosine kinase 1 (Sphingosine kinase) |
|
The sphingosine kinases (SPHK1 and SPHK2; SK1, SK2) are key enzymes within the sphingolipid metabolism pathway that promote tumour growth and pathologic inflammation. SK1-selective inhibitors include PF-543 [555-556] ... | ||
| sphingosine kinase 2 (Sphingosine kinase) |
|
The sphingosine kinases (SPHK1 and SPHK2; SK1, SK2) are key enzymes within the sphingolipid metabolism pathway that promote tumour growth and pathologic inflammation. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling, and is considered to be an anti-inflammatory enzyme with potential druggability for the treatment of autoimmune and inflammatory diseases [514] ... | ||
| spleen associated tyrosine kinase (Syk family) |
|
SYK plays a key role in coupling activated immunoreceptors to downstream cellular responses such as proliferation, differentiation, and phagocytosis. Mast cell, macrophage and B-cell activation (and release of inflammatory modulators) is disrupted by inhibition of SYK-mediated immunoreceptor signalling. Selective SYK inhibitors are being sought for a number of inflammatory conditions including rheumatoid arthritis, B-cell lymphoma and asthma/rhinitis [212,526] ... | ||
| SRC proto-oncogene, non-receptor tyrosine kinase (Src family) |
|
Src family tyrosine kinases act as general modulators of immune cell signaling, playing diverse signaling functions, both inhibitory and stimulatory, in immunoreceptor and integrin signaling pathways [377] ... | ||
| STIP1 homology and U-box containing protein 1 (E3 ubiquitin ligase components) |
|
STUB1 acts as a pivotal negative regulator of interferon-γ-mediated immune functions, via destabilisation of the ligand-receptor complex [21,174] ... | ||
| TANK binding kinase 1 (IKK family) |
|
TBK1 belongs to the IKK-kinase family of enzymes. It is a ubiquitously expressed serine/threonine protein kinase, and constitutes a key regulatory node for several signaling pathways involved in the innate immune response that lead to induction of type I interferons. Several classes of innate sensors including the TLRs and retinoic acid-inducible gene 1 (RIG-I)-like helicases engage TBK1-IRF3 signaling pathways to regulate transcription of type I IFNs. In neuroinflammation TBK1 is involved in TLR-dependent [307] ... | ||
| tec protein tyrosine kinase (Tec family) |
|
The TEC family protein tyrosine kinases have been identified as key components of T-cell-receptor activation and signalling. TEC family kinases are expressed predominantly by haematopoietic cells. T cells express ITK, TXK and TEC [53] ... | ||
| tripartite motif containing 21 (2.3.2.27 RING-type E3 ubiquitin transferase) |
|
Tripartite motif-containing (TRIM) superfamily proteins are critical in a variety of biological processes in innate immunity and are important for eradication of invading pathogens [474,516,657] ... | ||
| tripartite motif containing 38 (2.3.2.27 RING-type E3 ubiquitin transferase) |
|
TRIM38 catalyses the ubiquitination of Lys48 of the Toll-like receptor (TLR) adaptor protein TICAM1 (commonly referred to as TRIF) which mediates its proteosomal degradation. This action has been shown to inhibit TLR3-driven type I interferon signaling of the innate immune response [701] ... | ||
| TXK tyrosine kinase (Tec family) |
|
The TEC family protein tyrosine kinases have been identified as key components of T-cell-receptor activation and signalling. TEC family kinases are expressed predominantly by haematopoietic cells. T cells express ITK, TXK and TEC [53] ... | ||
| tyrosine kinase 2 (Janus kinase (JakA) family) |
|
TYK2 was the first member of the Janus kinase family to be identified. It associates with the cytoplasmic domain of type I and type II cytokine receptors, where it phosphorylates receptor subunits and facilitates signalling downstream of the receptors for the p40-containing cytokines IL-12 and IL-23 via activation of STAT-dependent transcription factors. It also mediates Type I IFN-driven responses [604] ... | ||
| vanin 1 (Hydrolases & Lipases) |
|
Mounting evidence indicates that vanin 1 is involved in inflammation associated with diseases including systemic lupus erythematosus [619] ... | ||
| YES proto-oncogene 1, Src family tyrosine kinase (Src family) |
|
Although primarily recognised for its oncogenic activity, we have iincluded YES1 in GtoImmuPdb based on its expression in cells of the immune system. | ||
| zeta chain of T cell receptor associated protein kinase 70 (Syk family) |
|
ZAP-70 has much lower intrinsic enzyme activity than SYK, and expression is restricted to T cells and NK cells [25] ... | ||
| Catalytic Receptors | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| 4-1BB (Tumour necrosis factor (TNF) receptor family) |
|
4-1BB is a costimulatory receptor that is highly expressed on both T cells and NK cells in the tumour environment. Since activation of 4-1BB produces an immunostimulatory effect that supports the immune cells involved in tumour control it is a target for immuno-oncology drug development [386] ... | ||
| AXL receptor tyrosine kinase (Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family) |
|
All three TAM family receptor tyrosine kinases are involved in regulating inflammatory responses through a negative feedback loop. Specifically, AXL-Gas6 signalling is reported to induce autophagy in murine macrophages via inhibition of the NLRP3 inflammasome, an effect which reduces hepatic inflammation in a mouse model [229] ... | ||
| BAFF receptor (Tumour necrosis factor (TNF) receptor family) |
|
This is a type III membrane bound receptor for B cell activating factor (BAFF). BAFF enhances B cell survival and hence regulates the peripheral B cell population. It is suggested that overproduction of BAFF may enhance the survival of autoreactive B cells, an effect which may contribute in the path ... | ||
| CD27 (Tumour necrosis factor (TNF) receptor family) |
|
CD27 (TNFRSF7) is a co-stimulatory immune checkpoint molecule that is expressed on various immune cells, including T cells and NK (natural killer) cells. The endogenous ligand for CD27 is CD70. CD27 interacts with various TRAF adaptor proteins and apoptosis regulatory protein SIVA (SIVA1). It has been recognized as playing an important role in priming, enhancing and sustaining a productive anti-cancer (CD8 T cell) adaptive immune response. CD27 is an immuno-oncology target [83,645] ... | ||
| CD40 (Immune checkpoint catalytic receptors, Tumour necrosis factor (TNF) receptor family) |
|
CD40 is a stimulatory receptor and a member of the tumor necrosis factor receptor superfamily (TNFRSF). It is expressed on a variety of immune cells, including macrophages, B cells, and dendritic cells (DCs). CD40 plays a key role in the activation of the immune system. Endogenous ligand is CD154 (C ... | ||
| Cytokine receptor-like factor 2 (IL-2 receptor family) |
|
Cytokine receptor-like factor 2 is the signal transducing subunit of the functional heterodimeric receptor for thymic stromal lymphopoietin (TSLP). Ligand binding is attributed to the interleukin-7 receptor subunit α. | ||
| death receptor 6 (Tumour necrosis factor (TNF) receptor family) |
|
Expressed predominantly in the thymus, spleen and white blood cells. May play a role in T helper cell activation, inflammation and immune regulation. Signals via the TRADD adaptor protein to the NF-κB and MAPK8/JNK pathways. | ||
| DExD/H-box helicase 58 (RIG-I-like receptor family) |
|
RIG-I is an intracellular sensor that responds to viral nucleic acids and activates downstream signaling, resulting in the induction of the type I interferon response [404] ... | ||
| DExH-box helicase 58 (RIG-I-like receptor family) |
|
LGP2 binds RNA but does not participate in the signaling pathway that RIG-1 and MDA5 are part of, and is assumed to provide a negative feedback for IFNβ induction by sequestering pathogen-derived RNA. | ||
| Fc fragment of IgE receptor Ia (Fc epsilon receptors) |
|
The product of the FCεR1A gene is a single-pass type I membrane protein that is a high-affinity receptor for immunoglobulin E (IgE). It is the ligand binding subunit of the tetrameric FCεRI, exhibiting a Kd of ~0.1nM. | ||
| Fc fragment of IgE receptor Ig (Fc epsilon receptors) |
|
The FCER1G protein is a gamma subunit that is utilised as part of the high affinity IgE receptor (a key complex involved in mediating allergic reactions) and other Fc receptors. | ||
| Fc fragment of IgE receptor II (Fc epsilon receptors) |
|
FcεRII (CD23) is the low-affinity receptor for immunoglobulin E (IgE) with a Kd > 100nM. This protein is a C-type lectin found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets. It has no structural similarities with other Fc receptors. FcεRII has functions as both a membrane-bound and as a soluble receptor [315,715] ... | ||
| fms related receptor tyrosine kinase 3 (Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family) |
|
FLT3 is the receptor for the cytokine Flt3 ligand (FLT3LG). Flt3 ligand is a growth factor akin to stem cell factor and colony stimulating factor 1, and is essential for hematopoietic progenitor cell development and expansion of both myeloid and lymphoid lineages. It is one of the growth factor receptors targeted by the chemotherapeutic tyrosine kinase inhibitor sorafenib. Results from mouse experiments suggest that Flt3 ligand is effective in treating sepsis, by potentiating innate immune functions of dendritic cells and neutrophils and improving T cell function [486] ... |
||
| herpes virus entry mediator (Immune checkpoint catalytic receptors, Tumour necrosis factor (TNF) receptor family) |
|
HSV viral envelope glycoprotein D (gD) binds to this protein and thereby gains entry to the cell. HVEM binds to several TRAFadaptor proteins to mediate intracellular signalling and activation of the immune response. | ||
| integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA-4 receptor) (Integrins) |
|
Integrin subunit alpha 4 is the alpha subunit of the α4β1 lymphocyte homing receptor. The cytoplasmic domain of α4 binds tightly to paxillin, a signaling adaptor protein, and this interaction promotes increased cell migration and inhibits cell spreading [230] ... | ||
| integrin, alpha L subunit (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide) (Integrins) |
|
ITGAL associates with the beta 2 chain (ITGB2) integrin and CD18 to form the lymphocyte function-associated antigen-1 (LFA-1) complex. LFA-1 is crucial for leukocyte intercellular adhesion and costimulatory signaling in the immune system. Ligands for LFA-1 are the intercellular adhesion molecules (ICAMs) 1-3. ITGAL is the target of the withdrawn psoriasis monoclonal antibody drug efalizumab ... | ||
| integrin, beta 2 subunit (complement component 3 receptor 3 and 4 subunit) (Integrins) |
|
ITGB2 is the beta component of the β2 integrins. It forms αβ heterodimers with the CD11 alpha subunits ITGAL (αL aka CD11a forming integrin LFA-1), ITGAM (αM aka CD11b, forming integrin Mac-1) and ITGAX (αX aka CD11c, forming integrin p150/95). Beta2-integrins are essential for leukocyte extravasation to sites of infection (i.e. leukocyte trafficking), and other immunological processes including neutrophil phagocytosis and ROS production, and T cell activation. Their absence causes a leukocyte adhesion deficiency, which manifests clinically as recurrent severe infections, defective wound healing and neutrophilia [321] ... | ||
| Interferon γ receptor 1 (Interferon receptor family) |
|
A subunit of the functional receptor for interferon γ. | ||
| Interferon γ receptor 2 (Interferon receptor family) |
|
A subunit of the functional receptor for interferon γ. | ||
| interferon induced with helicase C domain 1 (RIG-I-like receptor family) |
|
MDA5 is an intracellualar RNA sensor. It recognizes longer double-stranded RNA sequences than RIG-1. In autoimmunity, MDA5 has been specifically linked with type I diabetes and anti-MDA5 autoantibodies can be detected in patients with certain connective tissue autoimmune conditions [6,256,418] ... | ||
| Interleukin-12 receptor, β1 subunit (IL-12 receptor family) |
|
This protein is a subunit of both the IL-12 and IL-23 cytokine receptors. | ||
| Interleukin 13 receptor, α2 (IL-2 receptor family) |
|
Interleukin 13 receptor, α2 acts as a high affinity decoy receptor for interleukin 13 that sequesters the ligand away from IL13Rα1 and is involved in down-regulating IL-13 responses in vivo. IL13ra2 null mice exhibit enhanced IL-13 responses [692] ... | ||
| Interleukin-15 receptor subunit α (IL-2 receptor family) |
|
This is the ligand binding subunit of the functional IL-15 receptor complex. | ||
| Interleukin-18 receptor 1 (Immunoglobulin-like family of IL-1 receptors) |
|
Interleukin-18 1 protein (IL18R1) is the ligand binding subunit of the functional IL-18 receptor heterodimer. | ||
| Interleukin-1 receptor-like 1 (Immunoglobulin-like family of IL-1 receptors) |
|
IL1RL1 (ST2) is the ligand binding subunit of the functional receptor for IL-33. It is mainly expressed on mast cells, eosinophils and other immune cells [201] ... | ||
| Interleukin-1 receptor-like 2 (Immunoglobulin-like family of IL-1 receptors) |
|
Interleukin-1 receptor-like 2 is one of the subunits of the functional receptor for IL-36. An antibody that mimics IL-36RA's antagonist activity at the IL-36 receptor (MAB92) has been described [200] ... |
||
| Interleukin 20 receptor, β subunit (IL-10 receptor family) |
|
Interleukin 20 receptor, β subunit is a component of the functional receptor heterodimers for interleukins 19, 20 and 24. | ||
| Interleukin 21 receptor (IL-2 receptor family) |
|
This is the ligand binding subunit of the functional heterodimeric receptor for interleukin 21. | ||
| Interleukin 23 receptor (IL-12 receptor family) |
|
This is one of the subunits of the functional IL-23 receptor heterodimer. | ||
| Interleukin 27 receptor, alpha (IL-6 receptor family) |
|
This is the ligand binding subunit of the IL-27 receptor heterodimer, a complex with IL6ST (signal transducing subunit). | ||
| Interleukin-2 receptor subunit α (IL-2 receptor family) |
|
IL2RA is a ligand binding component of the IL-2R complex. This subunit is the molecular target of the approved biologics daclizumab (including daclizumab beta) and basiliximab. Another anti-CD25 mAb, inolimomab, has received orphan drug designation from the EMA, for the treatment of graft-versus-host disease. Phase 3 findings for this drug and indication are reported in [584] ... | ||
| Interleukin-2 receptor subunit γ (IL-2 receptor family) |
|
IL2RG is a common signal transducing subunit shared by the receptors for several different cytokines, namely the IL-2 receptor heterotrimer, the IL-4 receptor type I, the IL-7 receptor, the IL-9 receptor, the IL-15 receptor and the IL-21 receptor. | ||
| Interleukin-31 receptor, α subunit (IL-6 receptor family) |
|
|||
| Interleukin-4 receptor subunit α (IL-2 receptor family) |
|
IL4R is the common ligand binding subunit shared by the IL-4 receptors type I (receptor for IL-4) and type II (receptor for IL-4 and IL-13). A gain-of-function mutation in IL4R has been associated with atopy, enhanced B cell isotype switching from mu to epsilon and therefore elevated IgE levels [245] ... | ||
| Interleukin-6 receptor, α subunit (IL-6 receptor family) |
|
IL6R polymorphisms are associated with asthma risk [184] ... | ||
| Interleukin-6 receptor, β subunit (IL-6 receptor family) |
|
This is the common signal transducing subunit shared by members of the IL-6 family of cytokine receptors [537] ... | ||
| Interleukin-7 receptor subunit α (IL-2 receptor family) |
|
This is the ligand binding subunit of the functional IL-7 receptor complex. Effimmune are developing anti-IL7Rα monoclonal antibodies (e.g. OSE-127 [506] ... |
||
| KIT proto-oncogene, receptor tyrosine kinase (Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family) |
|
Stem cell factor (SCF) and its receptor KIT (c-KIT) play an essential part in mast cell biology. In addition to CSF/KIT-mediated regulation of mast cell development, proliferation and survival, KIT is also reported to be involved in the adhesion of mast cells to human airway epithelial cells (a homing and adhesion role), suggesting a mechanism that could be targeted for anti-asthmatic potential [221] ... | ||
| lymphotoxin β receptor (Tumour necrosis factor (TNF) receptor family) |
|
Interaction of the lymphotoxin β receptor (LTBR) with its ligand is required for the development and organization of the secondary lymphoid organs and is involved in chemokine release (reported to induce interleukin 8 gene expression [108] ... | ||
| MER proto-oncogene, tyrosine kinase (Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family) |
|
Mer plays a critical role in regulating self-tolerance mediated between apoptotic cells, dendritic cells, and T cells [50,662] ... | ||
| NLRC3 (NOD-like receptor family) |
|
NLRC3 is an intracellular pattern recognition receptor of the innate immune system. It has been shown to directly interact with and inhibit the type I interferon response of the intracellular DNA sensor STING to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses [391,733] ... | ||
| NLRC4 (NOD-like receptor family) |
|
As part of the innate inflammatory response to invading mobile bacteria, NLRC4 (Ipaf) in macrophages induces a pro-inflammatory response upon detection of cytosolic bacterial flagellin. In contrast, extracellular bacterial flagellin is detected by TLR5 [417] ... | ||
| NLRP1 (NOD-like receptor family) |
|
NLRP1 is a cytosolic sensor of bacterial infection and regulator of the resulting innate immune response [104] ... | ||
| NLRP3 (NOD-like receptor family) |
|
NLRP3 is a component of the NLRP3 inflammasome, a protein complex which activates caspase-1, and plays an important role in the regulation of inflammation and apoptosis (pyroptosis). Drug-like NLRP3 inhibitors are under investigation as novel therapeutics for the treatment of autoinflammatory diseases and neuroinflammation, as an alternative to anti-IL-1 therapies such as |
||
| NLRP6 (NOD-like receptor family) |
|
NLRP6 is an intracellular pattern recognition receptor (PRR). It is a member of the NACHT, LRR and PYD domains-containing protein (NALP) subfamily of PRRs. The presence of NALPs in inflammasomes underlies their involvement in regulating proinflammatory caspases (esp. caspase 1) ... | ||
| NLRX1 (NOD-like receptor family) |
|
NLRX1 is an intracellular pattern recognition receptor that plays a role in host immunity to certain bacterial infections. | ||
| nucleotide binding oligomerization domain containing 1 (NOD-like receptor family) |
|
NOD1 is an intracellular pattern recognition receptor that initiates an immune response to bacterial molecules containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. Mutations in NOD proteins are implicated in various inflammatory diseases associated with aberrant NF-κB activ ... |
||
| nucleotide binding oligomerization domain containing 2 (NOD-like receptor family) |
|
NOD2 is an intracellular pattern recognition receptor that initiates an immune response to bacterial molecules containing muramyl dipeptide (MDP). Mutations in NOD proteins are implicated in various inflammatory diseases associated with aberrant NF-κB activity; NF-κB being a major ... |
||
| OX40 (Tumour necrosis factor (TNF) receptor family) |
|
The OX40/OX40L axis is involved in late T cell costimulatory signalling and both partners are transiently expressed following antigen recognition. This checkpoint is particularly important for sustaining the effector function of Th1 and Th2 T cells. Blocking OX40/OX40L is reported to prevent the development of disease in in vivo autoimmune and inflammatory disease models [676] ... | ||
| RTP Type C (Receptor tyrosine phosphatase (RTP) family) |
|
CD45 is a high molecular weight cell surface glycoprotein expressed by cells of hematopoietic origin. Alternate transcripts lead to expression of isoforms that differ in their extracellular (ligand binding) domain (potentially facilitating differential and/or cell type specific biological functions [145] ... | ||
| TACI (Tumour necrosis factor (TNF) receptor family) |
|
TACI is a lymphocyte-specific TNF superfamily receptor expressed on B cells. Endogenous ligands include APRIL, BAFF and CAML. Defects in the function of TACI can underlie immunodeficiencies and autoimmune diseases. TACI ligands are molecular targets of approved and investigational biologics that are ... | ||
| TLR1 (Toll-like receptor family) |
|
TLR1/2 heterodimers detect and respond to bacterial triacyl lipopeptides [642] ... | ||
| TLR10 (Toll-like receptor family) |
|
To date, ligands and biological functions of human TLR10 remain unclear. However, evidence suggests it plays a modulatory role with predominantly inhibitory (anti-inflammatory) effects [470] ... | ||
| TLR2 (Toll-like receptor family) |
|
TLR1/2 and 2/6 heterodimers detect and initiate an immune response to triacylated and diacylated [438] ... | ||
| TLR3 (Toll-like receptor family) |
|
TLR3 is an endosomal anti-viral receptor [642] ... | ||
| TLR4 (Toll-like receptor family) |
|
TLR4 selectively responds to bacterial endotoxin, Gram-negative bacterial lipopolysaccharides (LPS), and lipooligosaccharides (LOS) [64,507] ... | ||
| TLR5 (Toll-like receptor family) |
|
TLR5 induces a pro-inflammatory response upon detection of extracellular bacterial flagellin from invading mobile bacteria [417] ... | ||
| TLR6 (Toll-like receptor family) |
|
TLR6 forms heterodimers with TLR2 to detect a wide range of bacterial lipopeptides (LP) from bacterial cell membranes, and effect an immune response [180] ... | ||
| TLR7 (Toll-like receptor family) |
|
TLR7 is an endosomal receptor detecting ssRNA [642] ... | ||
| TLR8 (Toll-like receptor family) |
|
TLR8 is an endosomal receptor detecting ssRNA [642] ... | ||
| TLR9 (Toll-like receptor family) |
|
TLR9 is an endosomal receptor detecting viral and bacterial CpG DNA and genomic DNA from some protozoan species [642] ... | ||
| transforming growth factor beta receptor 1 (Type I receptor serine/threonine kinases) |
|
The role of TGFBR1 in immuno-oncology is reviewed in [3] ... | ||
| tumor necrosis factor receptor 2 (Tumour necrosis factor (TNF) receptor family) |
|
TNFR2 is a receptor for lymphotoxin-α, and the membrane form of tumour necrosis factor (TNF). It plays a variety of important roles in immune system development and regulation [225,445] ... | ||
| TYRO3 protein tyrosine kinase (Type XI RTKs: TAM (TYRO3-, AXL- and MER-TK) receptor family) |
|
TYRO3 is a negative regulator of type 2 immunity [106] ... | ||
| Transporters | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| Anion exchange protein 2 (Anion exchangers) |
|
Ae2 is reported as a critical player in the regulation of CD8+ T cell intracellular pH homeostasis and immune response [128] ... | ||
| NRAMP1 (SLC11 family of proton-coupled metal ion transporters) |
|
NRAMP1 / SLC11A1 appears to be involved in macrophage antimicrobial action against intracellular pathogens, and although its precise mechanism is not fully resolved, evidence indicates its involvement in the activation of phagocytes and synthesis of proinflammatory cytokines. Polymorphisms in the human SLC11A1 gene have been associated with susceptibility to several infections [78,587,592] ... | ||
| Peptide transporter 3 (SLC15 family of peptide transporters) |
|
SLC15A3 and SLC15A4 are preferentially expressed by cells within the lymphatic system, including dendritic cells. Expression of these two genes is upregulated in response to TLR stimulation [437,588] ... | ||
| Peptide transporter 4 (SLC15 family of peptide transporters) |
|
SLC15A4 is an oligopeptide transporter that is expressed in early endosomes. It is critical for signalling via certain pattern recognition receptors (e.g. Toll-like receptors 7-9 and NOD receptors) in immune cell subsets [345] ... | ||
| Other Protein Targets | ||||
| GtoPdb receptor name (family) | Process Association Comments | GO Associations | Immunopharmacology Comments | |
| absent in melanoma 2 (Absent in melanoma (AIM)-like receptors (ALRs)) |
|
AIM2 primarily senses cytosolic DNA and initiates formation of an inflammasome to drive IL-1β cleavage and secretion. | ||
| advanced glycosylation end-product specific receptor (Immunoglobulin like domain containing proteins) |
|
RAGE is a single chain, membrane bound immunoglobulin type protein [442,553,703] ... | ||
| Aryl hydrocarbon receptor (Aryl hydrocarbon receptor) |
|
The AhR is activated by small signalling molecules derived from the diet, microorganisms and environmental agents, and when expressed by immune cells, it integrates the effects of the environment and metabolism on the immune response [540] ... | ||
| B7-H3 (CD276) (Other immune checkpoint proteins, CD molecules) |
|
B7-H3 is an immunoregulatory receptor involved in T cell activation and IFN-γ production [110,166] ... | ||
| baculoviral IAP repeat containing 2 (Inhibitors of apoptosis (IAP) protein family) |
|
Cellular inhibitors of apoptosis proteins BIRC2 and BIRC3 are required for efficient caspase-1 activation by the inflammasome [339] ... | ||
| baculoviral IAP repeat containing 3 (Inhibitors of apoptosis (IAP) protein family) |
|
Cellular inhibitor of apoptosis proteins (cIAPs) suppress apoptosis thereby promoting cell survival, and participate in the immune response (e.g. negative regulation of the necrosome, inflammasome and ripoptosome. In asthma, cIAPs extend the survival of neutrophils, macrophages and eosinophils, prolonging the inflammation. The minor alleles of single nucleotide polymorphisms in BIRC3 are shown to correlate with reduced numbers of circulating eosinophils and neutrophils, suggesting a protective effect against the development of asthma[536] ... | ||
| BCL2 apoptosis regulator (B-cell lymphoma 2 (Bcl-2) protein family) |
|
The role of Bcl-2 family members in immunity and disease is reviewed in [168] ... | ||
| BCL6 transcription repressor (BTB (POZ) domain containing TFs) |
|
BCL6/corepressor complexes are important for the formation of germinal centers and differentiation and proliferation of lymphocytes. Oncogenic mutations in BCL6 lead to the development of diffuse large B-cell lymphoma cells from germinal center B cells. Disruption of BCL6/corepressor complex formation by pharmacological inhibitors has therefore been identified as a novel drug mechanism with potential for the treatment of autoimmune diseases and cancer [94,102] ... | ||
| butyrophilin like 3 (Butyrophilin and butyrophilin-like proteins) |
|
BTNL3 and BTNL8 are two proteins expressed on the surface of human gut epithelial cells that are involved in shaping the constitution of gut resident dendritic γδ T cells [161] ... | ||
| butyrophilin like 8 (Butyrophilin and butyrophilin-like proteins) |
|
BTNL3 and BTNL8 are two proteins expressed on the surface of human gut epithelial cells that are involved in shaping the constitution of gut resident dendritic γδ T cells [161] ... | ||
| butyrophilin subfamily 3 member A1 (Butyrophilin and butyrophilin-like proteins) |
|
Vγ2Vδ2 (a.k.a. Vγ9Vδ2) T cells bridge the gap between innate and adaptive immunity and play roles in microbial immunity and tumour immunity [424] ... | ||
| CD14 molecule (CD molecules) |
|
Because of its key role in amplifying the immune response, CD14 was targeted for pharmacological modulation. Implicit Bioscience developed a first-in-class anti-CD14 monoclonal antbody (atibuclimab; IC14) as a clinical lead [595,656] ... | ||
| CD19 (CD molecules) |
|
CD19 is a B cell antigen used as a biomarker for normal and neoplastic B cells, and follicular dendritic cells. Anti-CD19 monoclonal antibodies are being investigated for potential clinical utility in oncology, transplantation and autimmune diseases (e.g. inebilizumab ... | ||
| CD1d molecule (CD molecules) |
|
CD1d is a lipid-binding MHC class I-like protein that is expressed by dendritic cells. CD1d presents self and microbial lipid/glycolipid antigens to unconventional T cells known as invariant natural killer T (iNKT) cells [115,689] ... | ||
| CD2 (CD molecules) |
|
CD2 is a cell surface glycoprotein expressed on most human T cells and natural killer (NK) cells [705] ... | ||
| CD209 molecule (C-type lectin-like receptors (CLRs)) |
|
DC-SIGN is a pathogen-recognition receptor involved in initiating the primary immune response to various viral and bacterial pathogens, as well as antigen presentation and initiation of the adaptive immune response. | ||
| CD20 (membrane-spanning 4-domains, subfamily A, member 1) (CD molecules) |
|
CD20 is a B cell antigen, involved in B cell development and maturation to antibody-producing plasma cells [132] ... | ||
| CD22 (Other immune checkpoint proteins, CD molecules, SIGLECs (conserved)) |
|
CD22 (SIGLEC2) is a B cell I-type (Ig-type) lectin that binds glycans containing sialic acids. It is involved in adhesion and activation, mediates B cell-B cell interactions and may be involved in the localisation of B cells in lymphoid tissues. Most SIGLECs inhibit immune cell activation, via | ||
| CD226 molecule (CD molecules) |
|
CD226 is an immunoglobulin-like adhesion molecule. It is a co-stimulatory partner for the PVR cell adhesion molecule (CD155). CD226 is expressed on T cells, NK cells and platelets. The CD155-CD226/TIGIT axis forms an immune checkpoint that has emerged as a target for tumour immunotherapy (to combat tumour immunoevasion) [480,694,740] ... | ||
| CD24 molecule (CD molecules) |
|
CD24 is a small GPI-anchored sialoglycoprotein that is expressed by immune cells. It is involved in B cell and T cell functions. CD24 binds to SIGLEC10 in an interaction that selectively suppresses the immune response to danger-associated molecular patterns (DAMPs). This latter action is being explo ... | ||
| CD28 (Other immune checkpoint proteins, CD molecules) |
|
CD28 is expressed on the surface of T cells and is required for the co-stimulatory signal essential for the activation, proliferation and survival of T cells, and Th2 cell development. CD28 acts in concert with the T cell receptor to stimulate cytokine release (promotes IL-2 production). CD28 binds the the B7 proteins CD80 and CD86 on the surface of antigen presenting cells to effect a co-stimulatory signal to T cells. In contrast, CTLA-4 delivers a co-inhibitory signal via CD80/CD86 [11] ... | ||
| CD300a (CD molecules) |
|
CD300a is a member of the CD300 family of leucocyte surface receptors [72] ... | ||
| CD33 (Other immune checkpoint proteins, CD33-related SIGLECs, CD molecules) |
|
CD33 (SIGLEC3) is a myeloid cell I-type (Ig-type) lectin that binds glycans containing sialic acids [208] ... | ||
| CD36 molecule (CD36 blood group) (CD molecules) |
|
CD36 expressed by macrophages plays a key role in the recognition and phagocytosis (scavenging) of multiple ligands that are recognised either as damage-associated molecular patterns (DAMPs) released by apoptotic cells, or as potentially dangerous pathogen-associated ligands. CD36 associates with specific Toll-like receptor (TLR) DAMP-detecting heterodimers when bound by certain ligands, and following internalisation of the ligand/CD36/TLR clusters, inflammatory responses (e.g. NF-κB-dependent production of CXCL1, CXCL2, CCL9 and CCL5, NLRP3 inflammasome-mediated IL-1B production, and NF-κB-dependent production of TNF in reponse to microbial diacylated lipopeptide) are triggered. Pharmacological modulation of CD36/TLR signalling is being explored as a strategy to suppress macrophage-driven inflammation [148,638,732] ... | ||
| CD38 (Abscisic acid receptor complex, CD molecules) |
|
CD38 is a type II transmembrane glycoprotein, that is widely expressed on immune cells and is involved in cell adhesion and signal transduction. Its extracellular domain acts as an ectoenzyme, catalyzing the conversion of nicotinamide adenine dinucleotide (NAD+) into nicotinamide, adenosine diphosphate-ribose (ADPR), and cyclic ADPR. Expression of CD38 is tightly regulated during B-cell development and maturation [228] ... | ||
| CD3e (CD molecules) |
|
CD3e is a subunit of the T cell receptor (TCR)-CD3 complex that mediates T cell receptor signal transduction in response to antigen detection. The TCR complex contains a CD3γ chain (CD3G), a CD3δ chain (CD3D), and two CD3ε chains (CD3E), plus the TCR (that can be α/β, or γ/δ type in the subsets of T cells named after the TCR they express) and the ζ-chain (zeta-chain). CD3e plays a crucial role in T cell development, highlighted by the discovery that defects in CD3e cause severe immunodeficiency [150,593] ... |
||
| CD4 (CD molecules) |
|
CD4 is being targeted for clinical utility in inflammatory diseases like rheumatoid arthritis (RA), neoplasms derived from T helper cells (T cell lymphomas and related malignancies), and for anti-HIV potential. Depending on the design of CD4 targeting antibodies, they can produce immunosuppressive effects via activation of Tregs and induction of tolerance, block HIV binding to CD4 to prevent HIV infection, or induce depletion of CD4+ T cells by apoptosis, ADCC, or CDC [328,658] ... | ||
| CD47 (CD molecules) |
|
CD47 belongs to the immunoglobulin superfamily and is reported to bind membrane integrins and the ligands thrombospondin 1 (THBS1) and signal-regulatory protein alpha (SIRPα). It is a ubiquitously expressed membrane protein that is a 'marker of self', and it is involved in self tolerance. Binding to SIRPα produces an anti-phagocytic signal. The CD47/THBS1 axis has been implicated in wound healing, and in the pathological progression of immune thrombocytopenia (ITP) [714] ... |
||
| CD55 molecule (Cromer blood group) (CD molecules) |
|
CD55 is a glycoprotein that is crucial for regulation of the complement cascade. Complement proteins are degraded when bound by CD55. Mutations in the CD55 gene drive excessive complement pathway activation that is observed in patients with the ultra-rare and life-threatening hereditary immune disea ... | ||
| CD6 (CD molecules) |
|
CD6 is a co-stimulatory molecule, predominantly expressed on lymphocytes and associated with autoimmune responses. CD6 interacts with activated leucocyte-cell adhesion molecule (ALCAM/CD166), found on antigen presenting cells. This interaction induces the production of proinflammatory cytokines [433] ... | ||
| CD74 (CD molecules) |
|
CD74 is a type II transmembrane glycoprotein which associates with the MHC class II α and β chains and directs the transport of class II molecules to lysosomal and endosomal compartments [133] ... | ||
| CD79B (CD molecules) |
|
CD79B is a component of the multimeric B cell antigen receptor (along with CD79A and a membrane-bound antibody that acts as the antigen recognition moiety). The CD79A/B component is responsible for signal transduction. The B cell antigen receptor complex is reported to be involved in the pathogenesis of various B cell-derived lymphoid cancers [428,560] ... | ||
| CD80 (Other immune checkpoint proteins, CD molecules) |
|
CD80 (B7-1) is expressed on dendritic cells and activated B cells and monocytes. It is required to provide a costimulatory signal necessary for T cell activation and survival. CD80 works in concert with CD86 to prime T cells. CD80 binds CD28 and CTLA-4 on T cells. It is the interaction with CTLA-4 t ... | ||
| CD86 (Other immune checkpoint proteins, CD molecules) |
|
CD86 (B7-2) is a type I membrane immunoglobulin. It is expressed on antigen-presenting cells and in association with CD80 provides the costimulatory signal necessary for T cell activation and survival. CD86 interacts with CD28 or CTLA-4 on T cells. It is the interaction with CTLA-4 that is targeted ... | ||
| copper metabolism domain containing 1 (COMMD proteins) |
|
COMMD1 has been shown to inhibit and/or attenuate signaling via NF-κB, a transcription factor with functions that affect innate and adaptive immunity, apoptosis, cell cycle regulation, and oncogenesis. | ||
| CREB binding lysine acetyltransferase (Non-enzymatic BRD containing proteins) |
|
CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. PMID: 26261308 ... | ||
| CS1 (CD319) (CD molecules) |
|
CS1 is a member of the signalling lymphocyte activation molecule (SLAM) receptor family. CS1 is a membrane glycoprotein primarily expressed on plasma cells. Homophilic interaction (i.e. interaction with itself) of CS1 induces B cell proliferation and autocrine cytokine secretion, thus playing a role in various immune functions. CS1 is a validated molecular target for the development of novel immunotherapeutics with the potential to treat MM, a malignant disease of plasma cells which remains incurable despite advances in treatment (such as bortezomib, lenalidomide and immunotherapies in clinical trial). Indeed, a combination therapy containing the anti-CS1 mAb elotuzumab (elotuzumab + lenalidomide + dexamethasone), was FDA approved for MM in 2015. CS1 expression is also elevated in patients with systemic lupus erythematosus (SLE) [318] ... |
||
| C-type lectin domain family 12 member A (C-type lectin-like receptors (CLRs)) |
|
The CLEC12A protein is a negative regulator of granulocyte and monocyte function [231,397] ... | ||
| C-type lectin domain family 4 member A (C-type lectin-like receptors (CLRs)) |
|
CLEC4A is an pattern recognition receptor and immunoreceptor that functions in cell adhesion, cell-cell signalling, glycoprotein turnover, and plays roles in inflammation and the immune response. It contains a immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. | ||
| C-type lectin domain family 4 member E (C-type lectin-like receptors (CLRs)) |
|
Mincle is an FcRγ-associated membrane receptor involved in initiating the innate immune response upon recognition of endogenous and exogenous ligands including Sin3A-associated protein (SAP130), α-mannan on fungal cell walls and mycobacterial cord factor (trehalose-6,6′-dimycolate (TDM)) [82] ... | ||
| C-type lectin domain family 6 member A (C-type lectin-like receptors (CLRs)) |
|
Dectin-2 is involved in initiating the innate immune response upon recognition of high mannose structures on fungal cell walls. It associates with the ITAM-containing FcRβ adaptor and signals through the Syk, PKCδ, and CARD9-Bcl10-MALT1 pathways to promote cytokine production in response ... | ||
| C-type lectin domain family 7 member A (C-type lectin-like receptors (CLRs)) |
|
Dectin-1 is a pattern recognition receptor involved in initiating the innate immune response upon recognition of various β(1,3)-linked and β(1,6)-linked glucans from fungi and plants. It mediates phagocytosis and the production of inflammatory mediators [81] ... | ||
| cytotoxic T-lymphocyte-associated protein 4 (CD152) (Other immune checkpoint proteins, CD molecules) |
|
CTLA-4 is expressed almost exclusively on CD4+ and CD8+ T cells. It functions as an immune checkpoint providing an inhibitory signal as a balance to stimulatory signals of the immune response i.e. it plays a crucial role in the maintenance of T cell homeostasis [411] ... | ||
| EP300 lysine acetyltransferase (Non-enzymatic BRD containing proteins) |
|
CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. PMID: 26261308 ... | ||
| Fc fragment of IgA receptor (Immunoglobulin like domain containing proteins, CD molecules) |
|
FcαRI is the cognate receptor for immunoglobulin A (IgA). In humans, IgA is predominantly expressed in the intestine, where it is important for maintaining mucosal homeostasis. IgA serves as a first-line defence to protect the gut epithelium from pathogens and enteric toxins [394,475] ... | ||
| Fc fragment of IgG receptor IIIa (Immunoglobulin like domain containing proteins, CD molecules) |
|
The FCGR3A gene is expressed by natural killer (NK) cells. The protein product (CD16A or FcγRIIIa) is an integral peptide-tethered membrane glycoprotein. FcγRIIIa is a low-affinity receptor for IgG Fc and is involved in removing antigen-antibody complexes from the circulation and antibody-dependent responses. FcγRIIIa is being exploited for drug development, specifically as a NK cell-engager to mediate NK effector cell killing of cancer cells. For example, Affimed have developed COVID-19: Analysis of blood from controls and COVID-19 patients was used to show that FcγRIIIa mediates phagocytosis of antibody-opsonised SARS-CoV-2 particles by human monocytes (and macrophages) [298] ... |
||
| Fc fragment of IgM receptor (Immunoglobulin like domain containing proteins) |
|
FcμRI is the cognate Fc receptor for immunoglobulin M (IgM) [335,374,572] ... | ||
| forkhead box N1 (Forkhead box TFs) |
|
FOXN1 deficiency has been identified as the cause of the nude severe combined immunodeficiency (SCID) phenotype in mice and humans [198,496] ... | ||
| heat shock protein 90 alpha family class B member 1 (Heat shock proteins) |
|
HSP90AB1 chaperones both JAK2 and PRKCE, and by ensuring proper folding of these kinase proteins it is involved in the phosphorylation/activation of STAT1 [119] ... | ||
| heat shock protein 90 beta family member 1 (Heat shock proteins) |
|
HSP90B1 is an endoplasmic reticulum chaperone required for proper folding and cell surface export of newly synthesized Toll-like receptor and integrin (CD11a, CD18 and CD49d) proteins. In its absence TLR responses are ablated, and there is no innate response to microbial stimuli [518] ... | ||
| ICOS (CD278) (Other immune checkpoint proteins, CD molecules) |
|
Inducible T cell costimulator (ICOS) and it's ligand constitute an immune checkpoint. ICOS is a surface receptor on activated T cells that binds its ligand on antigen presenting cells. Ligand-receptor interaction is a T cell activation signal. ICOS is a major regulator of the adaptive immune reponse that is structurally and functionally related to CD28 [268] ... | ||
| immunoglobulin heavy constant epsilon (Immunoglobulins) |
|
IgE is being investigated as a molecular target in allergic inflammatory conditions such as asthma, allergic rhinitis and chronic spontaneous urticaria. One anti-IgE monoclonal, omalizumab, has already been approved for use in patients with asthma or chronic spontaneous urticaria. Omalizumab binds t ... | ||
| immunoglobulin like domain containing receptor 2 (Other immune checkpoint proteins) |
|
ILDR2 has been identified as a novel inhibitory T cell immune checkpoint protein that belongs to the B7-like protein family [242] ... | ||
| interferon gamma inducible protein 16 (Absent in melanoma (AIM)-like receptors (ALRs)) |
|
IFI16 is a sensor for cytosolic DNA which induces type I interferon production via activation of the IRF3/NFκB pathway. | ||
| kelch like ECH-associated protein 1 (Kelch-like proteins) |
|
Transcription of many important detoxification enzymes is regulated by the Nrf2 transcription factor, which is (negatively) regulated by interaction with KEAP1, and when activated by disengagement from KEAP1, enters the nucleus and binds genes with an antioxidant responsive element (ARE) in their promoter sequences. Nrf2-responsive genes play important roles in the cellular defense system, in the regulation of the response to oxidative stress, and facilitate detoxification, antioxidant, cytoprotective and anti-inflammatory functions. Small molecule drug-like compounds that inhibit the KEAP1-Nrf2 protein-protein interaction (a.k.a. Nrf2 activators) are being developed for their potential anti-inflammatory action. The approved MS prodrug |
||
| killer cell lectin like receptor C1 (CD159a) (CD molecules) |
|
NKG2A (KLRC1; CD159a) acts as an inhibitory checkpoint receptor for HLA-E. NKG2A forms functional heterodimers with CD94 (KLRD1) to form a human leukocyte antigen E (HLA-E) recognition complex on a subset of natural killer (NK) cells and cytotoxic T cells. NKG2A/CD94/HLA-E binding suppresses immune vigilance, and overexpression of HLA-E is used by cancer cells to evade immune recognition and destruction [158,352,388,579] ... | ||
| killer cell lectin like receptor C2 (CD159c) (CD molecules) |
|
|||
| KIR3DL2 (CD158K) (CD molecules) |
|
KIR3DL2 mediates NK cell coinhibitory signals when it binds to MHC class I molecules on other cells. Binding to HLA-A3 , HLA-A11 [235] ... | ||
| LAG3 (CD223) (Other immune checkpoint proteins, CD molecules) |
|
Membrane-bound LAG3 (CD223) is a T cell inhibitory co-receptor and immune checkpoint being investigated as a cancer immunotherapeutic target [17,219] ... | ||
| leucine rich repeat containing 32 (Leucine-rich repeat proteins) |
|
GARP is expressed on the surface of T regulatory (Treg) cells and binds latent (inactive) TGF-β1. GARP is also involved in the activation of TGF-β1 [136] ... | ||
| leukocyte associated immunoglobulin like receptor 1 (CD305) (CD molecules) |
|
LAIR1 has been identified as a potential molecular receptor for Plasmodium falciparum-coded proteins that are expressed by infected host erythrocytes. Interaction of these parasite RIFIN proteins (encoded by rif genes) and inhibitory leucocyte receptors such as LAIR1 may mediate parasite-driven evasion of the host's immune system [546] ... | ||
| leukocyte immunoglobulin like receptor A4 (CD85g) (CD molecules) |
|
LILRA4 (CD85g) is a member of the activating leukocyte immunoglobulin like receptor (LILRA) family (HGNC family 1181). It is involved in activation of eosinophils and homeostatic regulation of the innate immunity of plasmacytoid dendritic cells (pDCs) [93] ... | ||
| leukocyte immunoglobulin like receptor B1 (CD85j) (CD molecules, Other immune checkpoint proteins) |
|
LILRB1 (CD85j) is a member of the inhibitory leukocyte immunoglobulin like receptor (LILRB) family (HGNC family 1182). It acts as an inhibitory immune checkpoint for B cell function. Ligands identified for LILRB include native MHC class I proteins, some HLA molecules, pathogen-derived ligands (e.g. from CMV, Dengue virus and some bacteria) and host immunomodulatory proteins such as S100 calcium binding protein A9 (S100A9; P06702; which also binds TLR4 and RAGE) [85] ... | ||
| lymphocyte antigen 96 (Lymphocyte antigens) |
|
LY96 (MD2) is a binding partner of Toll-like receptor 4 (TLR4), required to initiate an innate immune response to bacterial lipopolysaccharide (LPS). The signaling complex also contains CD14 co-receptor [322] ... | ||
| MALT1 paracaspase (Immunoglobulin like domain containing proteins) |
|
MALT1 inhibition is considered a tractable mechanism for the treatment of severe autoimmune diseases. The MALT1 inhibitory action of |
||
| myeloid cell nuclear differentiation antigen (Absent in melanoma (AIM)-like receptors (ALRs)) |
|
MNDA can be detected exclusively in nuclei of hematopoietic cells of the monocyte lineage. Expression is induced by interferon α [77] ... | ||
| Natural cytotoxicity triggering receptor 3 (CD337) (CD molecules) |
|
Activated by binding of extracellular ligands including BAG6 and NCR3LG1. Stimulates NK cells cytotoxicity toward neighboring cells producing these ligands. | ||
| NFKB inhibitor zeta (Inhibitors of NF-kappaB (IκB) family proteins) |
|
IκBζ is a key component of the immune response that regulates the transcription of a set of inflamatory genes through its association with the p50 or p52 subunits of NF-κB. IκBζ acts as an inhibitor of primary NF-κB response genes, but may also act as a coactivator of the expression of secondary response genes (through association with the NF-κB p50 subunit). IκBζ is in fact the product of a primary NF-κB reponse gene, being rapidly upregulated by various inflammatory stimuli. Pro-inflammatory gene products that are regulated by IκBζ include CCL2, IL-6, IL12p40, IL-17, IFNγ, and GM-CSF [293,311] ... | ||
| nuclear factor, erythroid 2 like 2 (Basic leucine zipper domain TFs) |
|
NRF2 is included in GToImmuPdb as mutations in this gene have been reported in patients with IMDDHH, an inherited disease in which some of the symptoms arise from defective immune system function [267] ... | ||
| perforin 1 (Cytolytic pore-forming proteins) |
|
Perforin 1 is expressed only in the secretory granules of cytotoxic T cells and natural killer (NK) cells, and it is an essential component of the immune system. These cell types release perforin 1 close to target cells (e.g. virus-infected and neoplastic cells) in process known as the granule exocytosis pathway [151] ... | ||
| polybromo 1 (Non-enzymatic BRD containing proteins) |
|
We have included PBRM1 in GtoImmuPdb as its repression has been reported to re-sensitise tumour cells with acquired resistance to immunotherapy (e.g. checkpoint blockade by anti-PD-1 or anti-CTLA-4 mAbs) to T cell-mediated attack [479] ... | ||
| programmed cell death 1 (CD279) (Other immune checkpoint proteins, CD molecules) |
|
Immune checkpoint blockade in oncology: Many types of cancer cells evolve mechanisms to evade control and elimination by the immune system. Such mechanisms can include inhibition of so-called 'immune checkpoints', which would normally be involved in the maintenance of immune homeostasis. An increasingly important area of clinical oncology research is the development of new agents which impede these evasion techniques, thereby switching immune vigilance back on, and effecting immune destruction of cancer cells. Three molecular targets of checkpoint inhibitors which are being extensively pursued are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Using antibody-based therapies targeting these pathways, clinical responses have been reported in various tumour types, including melanoma, renal cell carcinoma [476] ... |
||
| PVR related immunoglobulin domain containing (Other immune checkpoint proteins) |
|
PVRIG has been identified as a novel co-inhibitory immune checkpoint, that is exploited by some cancer cells to evade immune detection [431,683] ... | ||
| RAS guanyl releasing protein 1 (EF-hand domain containing proteins) |
|
RAS guanyl releasing protein 1 (RASGRP1) functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor. It activates Ras and the downstream Erk/MAP kinase cascade. RASGRP1 regulates the development, homeostasis and differentiation of T aand B cells [220,511,568] ... | ||
| RELA proto-oncogene, NF-kB subunit (NF-kappa B TF proteins) |
|
|||
| signal transducer and activator of transcription 3 (STAT transcription factors) |
|
STAT3 regulates the expression of a variety of genes in response to cytokines and growth factors (e.g. IFNs, EGF, IL-5, IL-6, HGF, LIF and BMP2) and plays important roles in several cellular processes, including cell growth and apoptosis. STAT3 is a crucial component of the JAK/STAT signalling pathway that is implicated in cancer and inflammation. STAT3 is frequently activated in cancers, where it downmodulates intrinsic immune surveillance of tumour cells. Phosphorylated (activated) STAT3 (pSTAT3) is a marker of poor cancer prognosis [719,726] ... | ||
| signal transducer and activator of transcription 6 (STAT transcription factors) |
|
STAT6 plays a central role in exerting IL-4 mediated biological responses. The prosurvival activity of the Th2 cytokine IL-4 is mediated by STAT6-dependent transcription of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL). This mechanism explains the resistance to apoptosis that is observed epithelial tumours which produce IL-4 [631] ... | ||
| SIRPA (CD172a) (CD molecules, Signal regulatory proteins) |
|
SIRPα is an important inhibitory immune response regulator. In interaction with CD47, SIRPα controls an inhibitory innate immune checkpoint that provides an anti-phagocytic (do not eat) signal. SIRPα is predominantly expressed by macrophages. Laboratory work has established that SIRPα is expressed by a subset of intestinal dendritic cells (integrin CD103+ DCs) that are critical for maintaining intestinal (mucosal) immune system homeostasis. This subset of CD103+SIRPα+ DCs selectively activates Th17 cells and type 3 innate lymphoid cells (ILC3) [291,673] ... | ||
| stimulator of interferon response cGAMP interactor 1 (Other pattern recognition receptors) |
|
STING functions as a major regulator of the innate immune response to viral and bacterial infections [373] ... | ||
| T-cell surface glycoprotein CD3 zeta chain (CD247) (CD molecules) |
|
Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. | ||
| TIGIT (Other immune checkpoint proteins, Immunoglobulin like domain containing proteins) |
|
TIGIT is now considered as an alternate inhibitory immune checkpoint protein which may have potential immunotherapeutic potential, particularly in conditions refractory to more established PD-1 checkpoint inhibition. Given its presence on T cells and NK cells, TIGIT offers an intervention point for targeting both the adaptive and innate arms of the immune system. Clinical development of anti-TIGIT monoclonal antibodies is in preliminary stages. Combination therapies with existing immune checkpoint inhibitors are considered particularly promising. MTIG7192A (NCT02794571 ... | ||
| TIM3 (CD366) (Other immune checkpoint proteins, CD molecules) |
|
TIM3 is an immunoglobulin type protein expressed exclusively on the surface of differentiated Th1 cells [423] ... | ||
| V-set immunoregulatory receptor (Other immune checkpoint proteins) |
|
V-set immunoregulatory receptor (VSIR) is commonly referred to as VISTA in the literature corpus. This is an Ig superfamily (B7 family) protein that acts as an inhibitory immune-checkpoint molecule. In common with other T cell co-inhibitory receptors (e.g. CTLA-4, PD-1, TIM3, and LAG3) it is involved in maintaining peripheral tolerance [358] ... | ||
| X-linked inhibitor of apoptosis (Inhibitors of apoptosis (IAP) protein family) |
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Mouse experiments suggest that XIAP regulates innate immune responses (to Listeria monocytogenes infection) by potentiating synergy between Toll-like receptors (TLRs) and NOD-like receptors (NLRs) through activation of JNK- and NF-κB-dependent signaling [47] ... | ||
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