Abstract
The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13353/full. G protein‐coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.
Conflict of interest
The authors state that there are no conflicts of interest to declare.
Overview
Catalytic receptors are cell‐surface proteins, usually dimeric in nature, which encompass ligand binding and functional domains in one polypeptide chain. The ligand binding domain is placed on the extracellular surface of the plasma membrane and separated from the functional domain by a single transmembrane‐spanning domain of 20‐25 hydrophobic amino acids. The functional domain on the intracellular face of the plasma membrane has catalytic activity, or interacts with particular enzymes, giving the superfamily of receptors its name. Endogenous agonists of the catalytic receptor superfamily are peptides or proteins, the binding of which may induce dimerization of the receptor, which is the functional version of the receptor.
Amongst the catalytic receptors, particular subfamilies may be readily identified dependent on the function of the enzymatic portion of the receptor. The smallest group is the particulate guanylyl cyclases of the natriuretic peptide receptor family. The most widely recognized group is probably the receptor tyrosine kinase (RTK) family, epitomized by the neurotrophin receptor family, where a crucial initial step is the activation of a signalling cascade by autophosphorylation of the receptor on intracellular tyrosine residue(s) catalyzed by enzyme activity intrinsic to the receptor. A third group is the extrinsic protein tyrosine kinase receptors, where the catalytic activity resides in a separate protein from the binding site. Examples of this group include the GDNF and ErbB receptor families, where one, catalytically silent, member of the heterodimer is activated upon binding the ligand, causing the second member of the heterodimer, lacking ligand binding capacity, to initiate signaling through tyrosine phosphorylation. A fourth group, the receptor threonine/serine kinase (RTSK) family, exemplified by TGF‐β and BMP receptors, has intrinsic serine/threonine protein kinase activity in the heterodimeric functional unit. A fifth group is the receptor tyrosine phosphatases (RTP), which appear to lack cognate ligands, but may be triggered by events such as cell:cell contact and have identified roles in the skeletal, hematopoietic and immune systems.
A sixth group of catalytic receptors in the Guide is the integrins, which have roles in cell:cell communication, often associated with signaling in the blood.
Family structure
5985 Prolactin receptor family
5986 Interferon receptor family
5988 Immunoglobulin‐like family of IL‐1 receptors
5994 Natriuretic peptide receptor family
5996 Pattern recognition receptors
5996 Toll‐like receptor family
5999 Receptor serine/threonine kinase (RSTK) family
6000 Type I receptor serine/threonine kinases
6001 Type II receptor serine/threonine kinases
6001 Type III receptor serine/threonine kinases
6002 RSTK functional heteromers
6003 Receptor tyrosine kinases
6004 Type I RTKs: ErbB (epidermal growth factor) receptor family
6005 Type II RTKs: Insulin receptor family
6005 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family
6007 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family
6008 Type V RTKs: FGF (fibroblast growth factor) receptor family
6009 Type VII RTKs: Neurotrophin receptor/Trk family
6010 Type VIII RTKs: ROR family
6010 Type X RTKs: HGF (hepatocyte growth factor) receptor family
6011 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family
6012 Type XII RTKs: TIE family of angiopoietin receptors
6012 Type XIII RTKs: Ephrin receptor family
6014 Type XVI RTKs: DDR (collagen receptor) family
6015 Type XVII RTKs: ROS receptors
6015 Type XVIII RTKs: LMR family
6016 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family
Cytokine receptor family
Overview
Cytokines are not a clearly defined group of agents, other than having an impact on immune signalling pathways, although many cytokines have effects on other systems, such as in development. A feature of some cytokines, which allows them to be distinguished from hormones, is that they may be produced by “non‐secretory” cells, for example, endothelial cells. Within the cytokine receptor family, some subfamilies may be identified, which are described elsewhere in the Guide to PHARMACOLOGY, receptors for the TNF family, the TGF‐β family and the chemokines. Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. These receptors possess a conserved extracellular region, known as the cytokine receptor homology domain (CHD), along with a range of other structural modules, including extracellular immunoglobulin (Ig)‐like and fibronectin type III (FBNIII)‐like domains, a transmembrane domain, and intracellular homology domains. An unusual feature of this group of agents is the existence of soluble and decoy receptors. These bind cytokines without allowing signalling to occur. A further attribute is the production of endogenous antagonist molecules, which bind to the receptors selectively and prevent signalling. A commonality of these families of receptors is the ligand‐induced homo‐ or hetero‐oligomerisation, which results in the recruitment of intracellular protein partners to evoke cellular responses, particularly in inflammatory or haematopoietic signalling. Although not an exclusive signalling pathway, a common feature of the majority of cytokine receptors is activation of the JAK/STAT pathway. This cascade is based around the protein tyrosine kinase activity of the Janus kinases (JAK), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo‐ or heterodimeric STATs function principally as transcription factors in the nucleus.
Type I cytokine receptors are characterized by two pairs of conserved cysteines linked via disulfide bonds and a C‐terminal WSXWS motif within their CHD. Type I receptors are commonly classified into five groups, based on sequence and structual homology of the receptor and its cytokine ligand, which is potentially more reflective of evolutionary relationships than an earlier scheme based on the use of common signal transducing chains within a receptor complex. These are the IL‐2, IL‐3, IL‐6, IL‐12 and prolactin families.
Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif. The type II cytokine receptors include the interferon, IL‐10, IL‐1 and IL‐17 receptors.
IL‐2 receptor family
Overview
The IL‐2 receptor family consists of one or more ligand‐selective subunits, and a common γ chain (γc): IL2RG, P31785), though IL‐4 and IL‐7 receptors can form complexes with other receptor chains. Receptors of this family associate with Jak1 and Jak3, primarily activating Stat5, although certain family members can also activate Stat1, Stat3, or Stat6. Ro264550 has been described as a selective IL‐2 receptor antagonist, which binds to IL‐2 177.
| Nomenclature | Interleukin 13 receptor, α2 | Interleukin‐15 receptor | Interleukin‐21 receptor | Thymic stromal lymphopoietin receptor |
| HGNC, UniProt | IL13RA2, Q14627 | – | – | – |
| Subunits | – | Interleukin‐2 receptor subunit β (Ligand‐binding subunit), Interleukin‐15 receptor subunit α (Ligand‐binding subunit), Interleukin‐2 receptor subunit γ (Other subunit) | Interleukin‐2 receptor subunit γ (Other subunit), Interleukin 21 receptor (Ligand‐binding subunit) | Cytokine receptor‐like factor 2 (Other subunit), Interleukin‐7 receptor subunit α (Ligand‐binding subunit) |
| Endogenous agonists | – | IL‐15 (IL15, P40933) | IL‐21 (IL21, Q9HBE4) | thymic stromal lymphopoietin (TSLP, Q969D9) |
| Comments | Decoy receptor that binds IL‐13 (IL13, P35225) as a monomer. | – | – | – |
Subunits
| Nomenclature | Interleukin‐2 receptor subunit α | Interleukin‐2 receptor subunit β | Interleukin‐2 receptor subunit γ | Interleukin‐4 receptor subunit α | Interleukin‐7 receptor subunit α |
| HGNC, UniProt | IL2RA, P01589 | IL2RB, P14784 | IL2RG, P31785 | IL4R, P24394 | IL7R, P16871 |
| Antibodies | daclizumab (Binding) (pK d>8) 154, basiliximab (Binding) | – | – | dupilumab (Binding) (pIC50 11.1) 121 | – |
IL‐3 receptor family
Overview
The IL‐3 receptor family signal through a receptor complex comprising of a ligand‐specific α subunit and a common β chain (CSF2RB, P32927), which is associated with Jak2 and signals primarily through Stat5.
| Nomenclature | Interleukin‐3 receptor | Interleukin‐5 receptor | Granulocyte macrophage colony‐stimulating factor receptor |
| Subunits | Interleukin 3 receptor, α subunit (Ligand‐binding subunit), Cytokine receptor common β subunit (Other subunit) | Interleukin 5 receptor, α subunit (Ligand‐binding subunit), Cytokine receptor common β subunit (Other subunit) | GM‐CSF receptor, α subunit (Ligand‐binding subunit), Cytokine receptor common β subunit (Other subunit) |
| Endogenous agonists | IL‐3 (IL3, P08700) | IL‐5 (IL5, P05113) | G‐CSF (CSF3, P09919), GM‐CSF (CSF2, P04141) |
| Selective antagonists | – | YM90709 [133] | – |
Subunits
| Nomenclature | Interleukin 3 receptor, α subunit | Interleukin 5 receptor, α subunit | GM‐CSF receptor, α subunit | Cytokine receptor common β subunit |
| HGNC, UniProt | IL3RA, P26951 | IL5RA, Q01344 | CSF2RA, P15509 | CSF2RB, P32927 |
| Endogenous agonists | IL‐3 (IL3, P08700) | IL‐5 (IL5, P05113) | GM‐CSF (CSF2, P04141) | – |
| Antibodies | – | benralizumab (Binding) (pK d 8.7) 93 | mavrilimumab (Binding) (pIC50 9.9) 29 | – |
IL‐6 receptor family
Overview
The IL‐6 receptor family signal through a ternary receptor complex consisting of the cognate receptor and either the IL‐6 signal transducer gp130 (IL6ST, P40189) or the oncostatin M‐specific receptor, β subunit (OSMR, Q99650), which then activates the JAK/STAT, Ras/Raf/MAPK and PI 3‐kinase/PKB signalling modules. Unusually amongst the cytokine receptors, the CNTF receptor is a glycerophosphatidylinositol‐linked protein.
| Nomenclature | Interleukin‐6 receptor | Interleukin‐11 receptor | Interleukin‐31 receptor | Ciliary neutrophic factor receptor |
| Subunits | Interleukin‐6 receptor, α subunit (Ligand‐binding subunit), Interleukin‐6 receptor, β subunit (Other subunit) | Interleukin‐11 receptor, α subunit (Ligand‐binding subunit), Interleukin‐6 receptor, β subunit (Other subunit) | Interleukin‐31 receptor, α subunit (Ligand‐binding subunit), Oncostatin M‐specific receptor, β subunit (Other subunit) | Leukemia inhibitory factor receptor (Other subunit), Interleukin‐6 receptor, β subunit, Ciliary neurotrophic factor receptor α subunit (Ligand‐binding subunit) |
| Endogenous agonists | IL‐6 (IL6, P05231) | IL‐11 (IL11, P20809) | IL‐31 (IL31, Q6EBC2) | CRCF1/CLCF1 heterodimer (CLCF1 CRLF1, O75462 Q9UBD9), ciliary neurotrophic factor (CNTF, P26441) |
| Agonists | – | oprelvekin | – | – |
| Antibodies | tocilizumab (Binding) (pK d 8.6) | – | – | – |
| Nomenclature | Leptin receptor | Leukemia inhibitory factor receptor | Oncostatin‐M receptor | Interleukin‐27 receptor |
| HGNC, UniProt | LEPR, P48357 | – | – | – |
| Subunits | – | Leukemia inhibitory factor receptor (Ligand‐binding subunit), Interleukin‐6 receptor, β subunit (Other subunit) | Interleukin‐6 receptor, β subunit (Other subunit), Oncostatin M‐specific receptor, β subunit (Ligand‐binding subunit) | Interleukin‐6 receptor, β subunit (Other subunit), Interleukin 27 receptor, alpha (Ligand‐binding subunit) |
| Endogenous agonists | leptin (LEP, P41159) | LIF (LIF, P15018), cardiotrophin‐1 (CTF1, Q16619), oncostatin M (OSM, P13725) | oncostatin M (OSM, P13725) | IL‐27 (EBI3 IL27, Q14213 Q8NEV9) |
Subunits
| Nomenclature | Interleukin‐6 receptor, α subunit | Interleukin‐6 receptor, β subunit | Interleukin‐11 receptor, α subunit | Interleukin 27 receptor, alpha |
| HGNC, UniProt | IL6R, P08887 | IL6ST, P40189 | IL11RA, Q14626 | IL27RA, Q6UWB1 |
| Antibodies | sarilumab (Binding) (pK d 10.6–11.1) 171 | – | – | – |
IL‐12 receptor family
Overview
IL‐12 receptors are a subfamily of the IL‐6 receptor family. IL12RB1 is shared between receptors for IL‐12 and IL‐23; the functional agonist at IL‐12 receptors is a heterodimer of IL‐12A/IL‐12B, while that for IL‐23 receptors is a heterodimer of IL‐12B/IL‐23A.
| Nomenclature | Interleukin‐12 receptor | Interleukin‐23 receptor | Interleukin‐12 receptor, β1subunit | Interleukin‐12 receptor, β2subunit | Interleukin 23 receptor |
| HGNC, UniProt | – | – | IL12RB1, P42701 | IL12RB2, Q99665 | IL23R, Q5VWK5 |
| Subunits | Interleukin‐12 receptor, β2 subunit (Other subunit), Interleukin‐12 receptor, β1 subunit (Ligand‐binding subunit) | Interleukin 23 receptor (Ligand‐binding subunit), Interleukin‐12 receptor, β1 subunit (Ligand‐binding subunit) | – | – | – |
| Endogenous agonists | IL‐12 (IL12A IL12B, P29459 P29460) | IL‐23 (IL12B IL23A, P29460) | – | – | – |
Prolactin receptor family
Overview
Prolactin family receptors form homodimers in the presence of their respective ligands, associate exclusively with Jak2 and signal via Stat5.
| Nomenclature | Eythropoietin receptor | Granulocyte colony‐stimulating factor receptor | Growth hormone receptor | Prolactin receptor | Thrombopoietin receptor |
| HGNC, UniProt | EPOR, P19235 | CSF3R, Q99062 | GHR, P10912 | PRLR, P16471 | MPL, P40238 |
| Endogenous agonists | erythropoietin (EPO, P01588) (Selective) (pIC50 11.1) [48] | G‐CSF (CSF3, P09919) | growth hormone 1 (GH1, P01241), growth hormone 2 (GH2, P01242) | choriomammotropin (CSH1 CSH2, P01243), chorionic somatomammotropinhormone‐like 1 (CSHL1, Q14406), prolactin (PRL, P01236) | thrombopoietin (THPO, P40225) |
| Agonists | peginesatide (pIC50 10.4) [48] | pegfilgrastim | – | – | romiplostim |
| Selective agonists | – | – | – | – | eltrombopag (pEC50 7.4) [119] |
| Antagonists | – | – | pegvisomant [180] | – | – |
Interferon receptor family
Overview
The interferon receptor family includes receptors for type I (α, β κ and ω) and type II (γ) interferons. There are at least 13 different genes encoding IFN‐α subunits in a cluster on human chromosome 9p22: α1 (IFNA1, P01562), α2 (IFNA2, P01563), α4 (IFNA4, P05014), α5 (IFNA5, P01569), α6 (IFNA6, P05013), α7 (IFNA7, P01567), α8 (IFNA8, P32881), α10 (IFNA10, P01566), α13 (IFNA13, P01562), α14 (IFNA14, P01570), α16 (IFNA16, P05015), α17 (IFNA17, P01571) and α21 (IFNA21, P01568).
| Nomenclature | Interferon‐α/β receptor | Interferon‐γ receptor |
| Subunits | Interferon α/β receptor 2 (Other subunit), interferon α/β receptor 1 (Ligand‐binding subunit) | Interferon γ receptor 2 (Other subunit), Interferon γ receptor 1 (Ligand‐binding subunit) |
| Endogenous agonists | IFN‐α1/13 (IFNA1 IFNA13, P01562), IFN‐α10 (IFNA10, P01566), IFN‐α14 (IFNA14, P01570), IFN‐α16 (IFNA16, P05015), IFN‐α17 (IFNA17, P01571), IFN‐α2 (IFNA2, P01563), IFN‐α21 (IFNA21, P01568), IFN‐α4 (IFNA4, P05014), IFN‐α5 (IFNA5, P01569), IFN‐α6 (IFNA6, P05013), IFN‐α7 (IFNA7, P01567), IFN‐α8 (IFNA8, P32881), IFN‐β (IFNB1, P01574), IFN‐κ (IFNK, Q9P0W0), IFN‐ω (IFNW1, P05000) | IFN‐γ (IFNG, P01579) |
| Selective agonists | peginterferon alfa‐2b [191] | – |
Subunits
| Nomenclature | interferon α/β receptor 1 | Interferon α/β receptor 2 | Interferon γ receptor 1 | Interferon γ receptor 2 |
| HGNC, UniProt | IFNAR1, P17181 | IFNAR2, P48551 | IFNGR1, P15260 | IFNGR2, P38484 |
| Selective agonists | peginterferon alfa‐2b [191] | – | – | – |
| Antibodies | anifrolumab (Binding) (pK d>10) 21 | – | – | – |
IL‐10 receptor family
Overview
The IL‐10 family of receptors are heterodimeric combinations of family members: IL10RA/IL10RB responds to IL‐10; IL20RA/IL20RB responds to IL‐19, IL‐20 and IL‐24; IL22RA1/IL20RB responds to IL‐20 and IL‐24; IL22RA1/IL10RB responds to IL‐22; IL28RA/IL10RB responds to IL‐28A, IL28B and IL‐29.
Subunits
Immunoglobulin‐like family of IL‐1 receptors
Overview
The immunoglobulin‐like family of IL‐1 receptors are heterodimeric receptors made up of a cognate receptor subunit and an IL‐1 receptor accessory protein, IL1RAP (Q9NPH3, also known as C3orf13, IL‐1RAcP, IL1R3). They are characterised by extracellular immunoglobulin‐like domains and an intracellular Toll/Interleukin‐1R (TIR) domain.
Subunits
IL‐17 receptor family
Overview
The IL17 cytokine family consists of six ligands (IL‐17A‐F), which signal through five receptors (IL‐17RA‐E).
| Nomenclature | Interleukin‐17 receptor | Interleukin‐25 receptor | Interleukin‐17C receptor |
| Subunits | Interleukin 17 receptor A (Ligand‐binding subunit), interleukin 17 receptor C (Other subunit) | Interleukin 17 receptor B (Ligand‐binding subunit), Interleukin 17 receptor A (Other subunit) | Interleukin 17 receptor A (Other subunit), Interleukin 17 receptor E (Ligand‐binding subunit) |
| Endogenous agonists | IL‐17A (IL17A, Q16552), IL‐17A/IL‐17F (IL17A IL17F, Q16552 Q96PD4), IL‐17F (IL17F, Q96PD4) | IL‐17B (IL17B, Q9UHF5), IL‐25 (IL25, Q9H293) | IL‐17C (IL17C, Q9P0M4) |
Subunits
| Nomenclature | Interleukin 17 receptor A | Interleukin 17 receptor B | interleukin 17 receptor C | Interleukin‐17 receptor D | Interleukin 17 receptor E |
| HGNC, UniProt | IL17RA, Q96F46 | IL17RB, Q9NRM6 | IL17RC, Q8NAC3 | IL17RD, Q8NFM7 | IL17RE, Q8NFR9 |
| Antibodies | brodalumab (Binding) (pK d 9.2) 179 | – | – | – | – |
| Comments | – | – | – | The endogenous agonist for this receptor is unknown. | – |
Further Reading
Broughton SE et al. (2012) The GM‐CSF/IL‐3/IL‐5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol. Rev. 250: 277‐302 [PMID:23046136]
Chang SH et al. (2011) Signaling of interleukin‐17 family cytokines in immunity and inflammation. Cell. Signal. 23: 1069‐75 [PMID:21130872]
George PM et al. (2012) Pharmacology and therapeutic potential of interferons. Pharmacol. Ther. 135: 44‐53 [PMID:22484806]
Gibbert K et al. (2013) IFN‐α subtypes: distinct biological activities in anti‐viral therapy. Br. J. Pharmacol. 168: 1048‐58 [PMID:23072338]
Mackall CL et al. (2011) Harnessing the biology of IL‐7 for therapeutic application. Nat. Rev. Immunol. 11: 330‐42 [PMID:21508983]
Mihara M et al. (2012) IL‐6/IL‐6 receptor system and its role in physiological and pathological conditions. Clin. Sci. 122: 143‐59 [PMID:22029668]
Miossec P et al. (2012) Targeting IL‐17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 11: 763‐76 [PMID:23023676]
Murugaiyan G et al. (2013) IL‐27 in tumor immunity and immunotherapy. Trends Mol Med 19: 108‐16 [PMID:23306374]
Palmer G et al. (2011) Interleukin‐33 biology with potential insights into human diseases. Nat Rev Rheumatol 7: 321‐9 [PMID:21519352]
Pappu R et al. (2011) The interleukin‐17 cytokine family: critical players in host defence and inflammatory diseases. Immunology 134: 8‐16 [PMID:21726218]
Rincon M. (2012) Interleukin‐6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol. 33: 571‐7 [PMID:22883707]
Rubino SJ et al. (2012) Innate IL‐17 and IL‐22 responses to enteric bacterial pathogens. Trends Immunol. 33: 112‐8 [PMID:22342740]
Tanaka T et al. (2012) Therapeutic targeting of the interleukin‐6 receptor. Annu. Rev. Pharmacol. Toxicol. 52: 199‐219 [PMID:21910626]
Wojno ED et al. (2012) New directions in the basic and translational biology of interleukin‐27. Trends Immunol. 33: 91‐7 [PMID:22177689]
Zhu S et al. (2012) IL‐17/IL‐17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin. Sci. 122: 487‐511 [PMID:22324470]
GDNF receptor family
Overview
GDNF family receptors (provisional nomenclature) are extrinsic tyrosine kinase receptors. Ligand binding to the extracellular domain of the glycosylphosphatidylinositol‐linked cell‐surface receptors (tabulated below) activates a transmembrane tyrosine kinase enzyme, RET (see Receptor Tyrosine Kinases). The endogenous ligands are typically dimeric, linked through disulphide bridges: glial cell‐derived neurotrophic factor GDNF (GDNF, P39905) (211 aa); neurturin (NRTN, Q99748) (197 aa); artemin (ARTN, Q5T4W7) (237 aa) and persephin (PSPN, O60542) (PSPN, 156 aa).
| Nomenclature | GDNF family receptor α1 | GDNF family receptor α2 | GDNF family receptor α3 | GDNF family receptor α4 |
| Common abreviation | GFRα1 | GFRα2 | GFRα3 | GFRα4 |
| HGNC, UniProt | GFRA1, P56159 | GFRA2, O00451 | GFRA3, O60609 | GFRA4, Q9GZZ7 |
| Potency order | GDNF (GDNF, P39905) >neurturin (NRTN, Q99748) >artemin (ARTN, Q5T4W7) | neurturin (NRTN, Q99748) >GDNF (GDNF, P39905) | artemin (ARTN, Q5T4W7) | persephin (PSPN, O60542) |
| Labelled ligands | [125I]GDNF (rat) (pK d 10.2–11.5) [92, 182] | – | – | – |
Comments
Inhibitors of other receptor tyrosine kinases, such as semaxanib, which inhibits VEGF receptor function, may also inhibit Ret function [131]. Mutations of RET and GDNF genes may be involved in Hirschsprung's disease, which is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.
Further Reading
Allen SJ et al. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138: 155‐75 [PMID:23348013]
Carnicella S et al. (2009) GDNF–a potential target to treat addiction. Pharmacol. Ther. 122: 9‐18 [PMID:19136027]
Liu H et al. (2012) Role of glial cell line‐derived neurotrophic factor in perineural invasion of pancreatic cancer. Biochim. Biophys. Acta 1826: 112‐20 [PMID:22503821]
Mickiewicz AL et al. (2011) GDNF family ligands: a potential future for Parkinson's disease therapy. CNS Neurol Disord Drug Targets 10: 703‐11 [PMID:21838676]
Pascual A et al. (2011) GDNF and protection of adult central catecholaminergic neurons. J. Mol. Endocrinol. 46: R83‐92 [PMID:21357726]
Rangasamy SB et al. (2010) Neurotrophic factor therapy for Parkinson's disease. Prog. Brain Res. 184: 237‐64 [PMID:20887879]
Integrins
Overview
Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the ‘Catalytic receptors’ section of the database until more stringent criteria from NC‐IUPHAR allows precise definition of their classification.
Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter‐receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I‐like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ ion in the I or I‐like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin‐linked kinase. Cellular activation regulates integrin ligand affinity via inside‐out signalling and ligand binding to integrins can regulate cellular activity via outside‐in signalling.
Comments: Integrin ligands
Collagen is the most abundant protein in metazoa, rich in glycine and proline residues, made up of cross‐linked triple helical structures, generated primarily by fibroblasts. Extensive post‐translational processing is conducted by prolyl and lysyl hydroxylases, as well as transglutaminases. Over 40 genes for collagen‐α subunits have been identified in the human genome. The collagen‐binding integrins α1β1, α2β1, α10β1 and α11β1 recognise a range of triple‐helical peptide motifs including GFOGER (O = hydroxyproline), a synthetic peptide derived from the primary sequence of collagen I (COL1A1 (COL1A1, P02452)) and collagen II (COL2A1 (COL2A1, P02458)).
Laminin is an extracellular glycoprotein composed of α, β and γ chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to α1β1, α2β1, α3,β1, α7β1 and α6β4 integrins10.
fibrinogen (FGA FGB FGG, P02671 P02675 P02679) is a glycosylated hexamer composed of two α (FGA, P02671), two β (FGB, P02675) and two γ (FGG, P02679,) subunits, linked by disulphide bridges. It is found in plasma and alpha granules of platelets. It forms cross‐links between activated platelets mediating aggregation by binding αIIbβ3; proteolysis by thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation cascade.
fibronectin (FN1, P02751) is a disulphide‐linked homodimer found as two major forms; a soluble dimeric form found in the plasma and a tissue version that is polymeric, which is secreted into the extracellular matrix by fibroblasts. Splice variation of the gene product (FN1, P02751) generates multiple isoforms.
vitronectin (VTN, P04004) is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide ‐linked dimer.
osteopontin (SPP1, P10451) forms an integral part of the mineralized matrix in bone, where it undergoes extensive post‐translation processing, including proteolysis and phosphorylation.
von Willebrand factor (VWF, P04275) is a glycoprotein synthesised in vascular endothelial cells as a disulphide‐linked homodimer, but multimerises further in plasma and is deposited on vessel wall collagen as a high molecular weight multimer. It is responsible for capturing platelets under arterial shear flow (via GPIb) and in thrombus propagation (via integrin αIIbβ3).
Subunits
Further Reading
Anthis NJ et al. (2011) The tail of integrin activation. Trends Biochem. Sci. 36: 191‐8 [PMID:21216149]
Hogg N et al. (2011) The insider's guide to leukocyte integrin signalling and function. Nat. Rev. Immunol. 11: 416‐26 [PMID:21597477]
Hynes RO. (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110: 673‐87 [PMID:12297042]
Ivaska J et al. (2011) Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu. Rev. Cell Dev. Biol. 27: 291‐320 [PMID:21663443]
Shattil SJ et al. (2010) The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol. 11: 288‐300 [PMID:20308986]
Wickström SA et al. (2011) Regulation of membrane traffic by integrin signaling. Trends Cell Biol. 21: 266‐73 [PMID:21440440]
Natriuretic peptide receptor family
Overview
Natriuretic peptide receptors (provisional nomenclature) are a family of homodimeric, catalytic receptors with a single TM domain and guanylyl cyclase (EC 4.6.1.2) activity on the intracellular domain of the protein sequence. Isoforms are activated by the peptide hormones atrial natriuretic peptide (NPPA, P01160), brain natriuretic peptide (NPPB, P16860) and C‐type natriuretic peptide (NPPC, P23582). Another family member is GC‐C, the receptor for guanylin (GUCA2A, Q02747) and uroguanylin (GUCA2B, Q16661) . Family members have conserved ligand‐binding, catalytic (guanylyl cyclase) and regulatory domains with the exception of NPR‐C which has an extracellular binding domain homologous to that of other NPRs, but with a truncated intracellular domain which appears to couple, via the Gi/o family of G‐proteins, to activation of phospholipase C, inwardly‐rectifying potassium channels and inhibition of adenylyl cyclase activity [136].
Comments
The polysaccharide obtained from fermentation of Aureobasidium species, HS142‐1, acts as an antagonist at both NPR‐A and NPR‐B receptors [132].
GUCY2D (RetGC1, GC‐E, Q02846) and GUCY2F (RetGC2, GC‐F, P51841) are predominantly retinal guanylyl cyclase activities, which are inhibited by calcium ions acting through the guanylyl cyclase activating peptides GCAP1 (GUCA1A, 43080), GCAP2 (GUCA1B, Q9UMX6) and GCAP3 (GUCA1C, O95843) [78].
Further Reading
Kuhn M. (2012) Endothelial actions of atrial and B‐type natriuretic peptides. Br. J. Pharmacol. 166: 522‐31 [PMID:22220582]
Misono KS et al. (2011) Structure, signaling mechanism and regulation of the natriuretic peptide receptor guanylate cyclase. FEBS J. 278: 1818‐29 [PMID:21375693]
Pandey KN. (2011) The functional genomics of guanylyl cyclase/natriuretic peptide receptor‐A: perspectives and paradigms. FEBS J. 278: 1792‐807 [PMID:21375691]
Potter LR. (2011) Natriuretic peptide metabolism, clearance and degradation. FEBS J. 278: 1808‐17 [PMID:21375692]
Potter LR. (2011) Regulation and therapeutic targeting of peptide‐activated receptor guanylyl cyclases. Pharmacol. Ther. 130: 71‐82 [PMID:21185863]
Potter LR. (2011) Guanylyl cyclase structure, function and regulation. Cell. Signal. 23: 1921‐6 [PMID:21914472]
Pattern recognition receptors
Overview
Pattern Recognition Receptors (PRRs, [174]) (nomenclature as agreed by NC‐IUPHAR sub‐committee on Pattern Recognition Receptors, [18]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs include both cell‐surface and intracellular proteins, including toll‐like receptors (TLRs), nucleotide‐binding oligomerization domain‐like receptors (NLRs, also known as NOD‐like receptors) and the mannose receptor family (ENSFM00250000004089). PRRs may be divided into signalling‐associated members, identified here, and endocytic members (such as the mannose receptor family), the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction.
PRRs express multiple leucine‐rich regions to bind a range of microbially‐derived ligands, termed PAMPs or pathogen‐associated molecular patterns, which includes peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids.
Further Reading
Bryant CE et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 [PMID:25829385]
Davis BK et al. (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29: 707‐35 [PMID:21219188]
Ting JP et al. (2008) The NLR gene family: a standard nomenclature. Immunity 28: 285‐7 [PMID:18341998]
Toll‐like receptor family
Overview
Members of the toll‐like family of receptors (nomenclature recommended by the NC‐IUPHAR subcommittee on pattern recognition receptors, [18]) share significant homology with the interleukin‐1 receptor family and appear to require dimerization either as homo‐ or heterodimers for functional activity. Heterodimerization appears to influence the potency of ligand binding substantially (e.g. TLR1/2 and TLR2/6, [175, 176]). TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11 are cell‐surface proteins, while other members are associated with intracellular organelles, signalling through the MyD88‐dependent pathways (with the exception of TLR3). As well as responding to exogenous infectious agents, it has been suggested that selected members of the family may be activated by endogenous ligands, such as hsp60 (HSPD1, P10809) [141].
| Nomenclature | TLR1 | TLR2 | TLR3 | TLR4 | TLR5 |
| HGNC, UniProt | TLR1, Q15399 | TLR2, O60603 | TLR3, O15455 | TLR4, O00206 | TLR5, O60602 |
| Agonists | – | peptidoglycan [165, 205] | polyIC [6] | LPS [150], paclitaxel [85] | flagellin [69] |
| Comments | Functions as a heterodimer with TLR2 in detection of triacylated lipoproteins. Activated by the synthetic analogue Pam3CSK4. | Functions as a heterodimer with either TLR1 or TLR6 in the detection of triacylated and diacylated lipopeptides respectively. TLR1/2 and 2/6 heterodimers can be activated by the synthetic lipopeptides Pam3CSK4 and Pam2CSK4 respectively. There is some debate in the field as to whether or not peptidoglycan is a direct agonist of TLR2, or whether the early studies reporting this contained contaminating lipoproteins. | Involved in endosomal detection of dsRNA; pro‐inflammatory. | eritoran (E5564) is a lipid A analogue, which has been described as a TLR4 antagonist [80]. TLR4 signals in conjunction with the co‐factor MD2. | Involved in the detection of bacterial flagellin; pro‐inflammatory. |
| Nomenclature | TLR6 | TLR7 | TLR8 | TLR9 | TLR10 | TLR11 |
| HGNC, UniProt | TLR6, Q9Y2C9 | TLR7, Q9NYK1 | TLR8, Q9NR97 | TLR9, Q9NR96 | TLR10, Q9BXR5 | – |
| Agonists | – | imiquimod [72], loxoribine [70], resiquimod [72] | imiquimod, resiquimod [72] | – | – | – |
| Antagonists | – | hydroxychloroquine (pIC50 5.6) [98] | – | hydroxychloroquine (pIC50 7.1) [98] | – | – |
| Comments | Functions as a heterodimer with TLR2. Involved in the pro‐inflammatory response to diacylated bacterial lipopeptides. | Activated by imidazoquinoline derivatives and RNA oligoribonucleotides. Involved in endosomal detection of ssRNA; pro‐inflammatory. | Activated by imidazoquinoline derivatives and RNA oligoribonucleotides. Endosomal detection of ssRNA; pro‐inflammatory. | Toll‐like receptor 9 interacts with unmethylated CpG dinucleotides from bacterial DNA [73]. Activated by CpG rich DNA sequences; pro‐inflammatory. | Murine TLR10 has a retroviral insertion that makes in non‐functional. | Found in mouse |
Further Reading
Bryant CE et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 [PMID:25829385]
NOD‐like receptor family
Overview
The nucleotide‐binding oligomerization domain, leucine‐rich repeat (NLR) family of receptors (nomenclature recommended by the NC‐IUPHAR subcommittee on pattern recognition receptors [18]) share a common domain organisation. This consists of an N‐terminal effector domain, a central nucleotide‐binding and oligomerization domain (NOD; also referred to as a NACHT domain), and C‐terminal leucine‐rich repeats (LRR) which have regulatory and ligand recognition functions. The type of effector domain has resulted in the division of NLR family members into two major sub‐families, NLRC and NLRP, along with three smaller sub‐families NLRA, NLRB and NLRX [178]. NLRC members express an N‐terminal caspase recruitment domain (CARD) and NLRP members an N‐terminal Pyrin domain (PYD).
Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase RIPK2 (receptor interacting serine/threonine kinase 2, O43353, also known as CARD3, CARDIAK, RICK, RIP2) leading to signalling through NFκB and MAP kinase. Activation of NLRC4 (previously known as IPAF) and members of the NLRP3 family, including NLRP1 and NLRP3, leads to formation of a large multiprotein complex known as the inflammasome. In addition to NLR proteins other key members of the inflammasome include the adaptor protein ASC (apoptosis‐associated speck‐like protein containing a CARD, also known as PYCARD, CARD5, TMS1, Q9ULZ3) and inflammatory caspases. The inflammasome activates the pro‐inflammatory cytokines IL‐1β (IL1B, P01584) and IL‐18 (IL18, Q14116) [18, 37].
| Nomenclature | nucleotide‐binding oligomerizationdomain containing 1 | nucleotide‐binding oligomerization domain containing 2 | NLRC3 | NLRC4 | NLRC5 |
| Common abreviation | NOD1 | NOD2 | – | – | – |
| HGNC, UniProt | NOD1, Q9Y239 | NOD2, Q9HC29 | NLRC3, Q7RTR2 | NLRC4, Q9NPP4 | NLRC5, Q86WI3 |
| Agonists | meso‐DAP | muramyl dipeptide | – | – | – |
| Comments | – | NOD2 has also been reported to be activated by ssRNA [160] although this has not been widely reproduced. | – | NLRC4 forms an inflammasome in conjunction with the NAIP proteins and responds to bacterial flagellin and type III secretion system rod proteins. | – |
| Nomenclature | NLRX1 | CIITA | NLRP1 | NLRP2 |
| HGNC, UniProt | NLRX1, Q86UT6 | CIITA, P33076 | NLRP1, Q9C000 | NLRP2, Q9NX02 |
| Agonists | – | – | muramyl dipeptide | – |
| Comments | – | – | NLRP1 has 3 murine orthologues which lack the N‐terminal Pyrin domain. Murine NLRP1b (ENSMUSG00000070390) is the best characterised, responding to Anthrax Lethal Toxin. | Along with NLRP7, NLRP2 is the product of a primate‐specific gene duplication. |
| Nomenclature | NLRP3 | NLRP4 | NLRP5 | NLRP6 |
| HGNC, UniProt | NLRP3, Q96P20 | NLRP4, Q96MN2 | NLRP5, P59047 | NLRP6, P59044 |
| Inhibitors | MCC950 (pIC50>8) [30] | – | – | – |
| Comments | Multiple virus particles have been shown to act as agonists, including Sendai and influenza. NLRP3 has been shown to be activated following disruption of cellular haemostasis by a wide‐variety of exogenous and endogenous molecules. The identity of the precise agonist that interacts with NLRP3 remains enigmatic. | Expanded in the mouse resulting in 7 orthologues. | – | – |
Comments
NLRP3 has also been reported to respond to host‐derived products, known as danger‐associated molecular patterns, or DAMPs, including uric acid [122], ATP, L‐glucose, hyaluronan and amyloid β (APP, P05067) [163].
Loss‐of‐function mutations of NLRP3 are associated with cold autoinflammatory and Muckle‐Wells syndromes.
This family also includes NLR family, apoptosis inhibitory protein (NAIP, Q13075) which can be found in the 'Inhibitors of apoptosis (IAP) protein family' in the Other protein targets section of the Guide.
Further Reading
Bryant CE et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 [PMID:25829385]
Receptor serine/threonine kinase (RSTK) family
Overview
Receptor serine/threonine kinases (RTSK), EC 2.7.11.30, respond to particular cytokines, the transforming growth factor β(TGFβ) and bone morphogenetic protein (BMP) families, and may be divided into two subfamilies on the basis of structural similarities. Agonist binding initiates formation of a cell‐surface complex of type I and type II RSTK, possibly heterotetrameric, where where both subunits express serine/threonine kinase activity. The type I receptor serine/threonine kinases are also known as activin receptors or activin receptor‐like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1‐7). The type II protein phosphorylates the kinase domain of the type I partner (sometimes referred to as the signal propagating subunit), causing displacement of the protein partners, such as the FKBP12 FK506‐binding protein FKBP1A (P62942) and allowing the binding and phosphorylation of particular members of the Smad family. These migrate to the nucleus and act as complexes to regulate gene transcription. Type III receptors, sometimes called co‐receptors or accessory proteins, regulate the signalling of the receptor complex, in either enhancing (for example, presenting the ligand to the receptor) or inhibitory manners. TGFβ family ligand signalling may be inhibited by endogenous proteins, such as follistatin (FST, P19883), which binds and neutralizes activins to prevent activation of the target receptors.
Endogenous agonists, approximately 30 in man, are often described as paracrine messengers acting close to the source of production. They are characterized by six conserved cysteine residues and are divided into two subfamilies on the basis of sequence comparison and signalling pathways activated, the TGFβ/activin/nodal subfamily and the BMP/GDF (growth/differentiation factor)/MIS (Müllerian inhibiting substance) subfamily. Ligands active at RSTKs appear to be generated as large precursors which undergo complex maturation processes [105]. Some are known to form disulphide‐linked homo‐ and/or heterodimeric complexes. Thus, inhibins are α subunits linked to a variety of β chains, while activins are combinations of β subunits.
Comments
A number of endogenous inhibitory ligands have been identified for RSTKs, including BMP‐3 (BMP3, P12645), inhibin α (INHA, P05111), inhibin βC (INHBC, P55103) and inhibin βE (INHBE, P58166).
An appraisal of small molecule inhibitors of TGFβ and BMP signalling concluded that TGFβ pathway inhibitors were more selective than BMP signalling inhibitors [186]. The authors confirmed the selectivity of TGF‐beta RI inhibitor III to inhibit TGFβ signalling through ALK4, ALK5, ALK7 [36]. Dorsomorphin inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [209].
Smads were identified as mammalian orthologues of Drosophila genes termed “mothers against decapentaplegic” and may be divided into Receptor‐regulated Smads (R‐Smads, including Smad1, Smad2, Smad3, Smad5 and Smad8), Co‐mediated Smad (Co‐Smad, Smad4) and Inhibitory Smads (I‐Smad, Smad6 and Smad7). R‐Smads form heteromeric complexes with Co‐Smad. I‐Smads compete for binding of R‐Smad with both receptors and Co‐Smad.
Further Reading
Ehrlich M et al. (2011) Homomeric and heteromeric complexes among TGF‐β and BMP receptors and their roles in signaling. Cell. Signal. 23: 1424‐32 [PMID:21515362]
Hinck AP. (2012) Structural studies of the TGF‐βs and their receptors ‐ insights into evolution of the TGF‐β superfamily. FEBS Lett. 586: 1860‐70 [PMID:22651914]
Massagué J. (2012) TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 13: 616‐30 [PMID:22992590]
Moustakas A et al. (2009) The regulation of TGFbeta signal transduction. Development 136: 3699‐714 [PMID:19855013]
Rider CC et al. (2010) Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. Biochem. J. 429: 1‐12 [PMID:20545624]
Santibañez JF et al. (2011) TGF‐β/TGF‐β receptor system and its role in physiological and pathological conditions. Clin. Sci. 121: 233‐51 [PMID:21615335]
Xu P et al. (2012) Post‐translational regulation of TGF‐β receptor and Smad signaling. FEBS Lett. 586: 1871‐84 [PMID:22617150]
Type I receptor serine/threonine kinases
Overview
The type I receptor serine/threonine kinases are also known as activin receptors or activin receptor‐like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1‐7).
| Nomenclature | activin A receptor type II‐like 1 | activin A receptor, type I | bone morphogenetic protein receptor, type IA | activin A receptor, type IB |
| Common abreviation | ALK1 | ALK2 | BMPR1A | ALK4 |
| HGNC, UniProt | ACVRL1, P37023 | ACVR1, Q04771 | BMPR1A, P36894 | ACVR1B, P36896 |
| EC number | 2.7.11.30 | 2.7.11.30 | 2.7.11.30 | 2.7.11.30 |
| Inhibitors | compound 13d [PMID: 23639540] (pIC50>8.3) [45], compound 13r [PMID: 23639540] (pIC50>8.3) [45] | compound 13d [PMID: 23639540] (pIC50>8.3) [45], ML347 (pIC50 7.5) [45] | compound 13d [PMID: 23639540] (pIC50>8.3) [45] | – |
| Selective inhibitors | – | – | – | EW‐7197 (pIC50 7.9) [82] |
| Nomenclature | transforming growth factor, beta receptor 1 | bone morphogenetic protein receptor, type IB | activin A receptor, type IC |
| Common abreviation | TGFBR1 | BMPR1B | ALK7 |
| HGNC, UniProt | TGFBR1, P36897 | BMPR1B, O00238 | ACVR1C, Q8NER5 |
| EC number | 2.7.11.30 | 2.7.11.30 | 2.7.11.30 |
| Inhibitors | LY2109761 (pK i 7.4) [125], compound 15b [PMID: 16539403] (pIC50 7.1) [104] | compound 13d [PMID: 23639540] (pIC50>8.3) [45] | – |
| Selective inhibitors | EW‐7197 (pIC50 8) [82] | – | – |
Type II receptor serine/threonine kinases
| Nomenclature | activin A receptor, type IIA | activin A receptor, type IIB | anti‐Mullerian hormone receptor, type II | bone morphogenetic protein receptor, type II (serine/threonine kinase) | transforming growth factor, beta receptor II (70/80kDa) |
| Common abreviation | ActR2 | ActR2B | MISR2 | BMPR2 | TGFBR2 |
| HGNC, UniProt | ACVR2A, P27037 | ACVR2B, Q13705 | AMHR2, Q16671 | BMPR2, Q13873 | TGFBR2, P37173 |
| EC number | 2.7.11.30 | 2.7.11.30 | 2.7.11.30 | 2.7.11.30 | 2.7.11.30 |
| Inhibitors | – | – | – | – | compound 13d [PMID: 23639540] (pIC50 7.6) [45] |
| Antibodies | – | bimagrumab (Binding) (pK d 11.8) 12 | – | – | – |
Type III receptor serine/threonine kinases
| Nomenclature | transforming growth factor, beta receptor III |
| Common abreviation | TGFBR3 |
| HGNC, UniProt | TGFBR3, Q03167 |
RSTK functional heteromers
Overview
For the receptors listed on this page, the exact combination of subunits forming the functional heteromeric receptors is unknown.
Receptor tyrosine kinases
Overview
Receptor tyrosine kinases (RTKs), a family of cell‐surface receptors, which transduce signals to polypeptide and protein hormones, cytokines and growth factors are key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, cell migration and cell cycle control [14, 62, 184]. In the human genome, 58 RTKs have been identified, which fall into 20 families [102].
All RTKs display an extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity (occasionally split into two domains by an insertion, termed the kinase insertion), with juxta‐membrane and C‐terminal regulatory regions. Agonist binding to the extracellular domain evokes dimerization, and sometimes oligomerization, of RTKs (a small subset of RTKs forms multimers even in the absence of activating ligand). This leads to autophosphorylation in the tyrosine kinase domain in a trans orientation, serving as a site of assembly of protein complexes and stimulation of multiple signal transduction pathways, including phospholipase C‐γ, mitogen‐activated protein kinases and phosphatidylinositol 3‐kinase [184].
RTKs are of widespread interest not only through physiological functions, but also as drug targets in many types of cancer and other disease states. Many diseases result from genetic changes or abnormalities that either alter the activity, abundance, cellular distribution and/or regulation of RTKs. Therefore, drugs that modify the dysregulated functions of these RTKs have been developed which fall into two categories. One group is often described as ‘biologicals’, which block the activation of RTKs directly or by chelating the cognate ligands, while the second are small molecules designed to inhibit the tyrosine kinase activity directly.
Further Reading
Alsina FC et al. (2012) New insights into the control of neurotrophic growth factor receptor signaling: implications for nervous system development and repair. J. Neurochem. 123: 652‐61 [PMID:22994539]
Arteaga CL et al. (2012) Treatment of HER2‐positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9: 16‐32 [PMID:22124364]
Camidge DR et al. (2012) Treating ALK‐positive lung cancer–early successes and future challenges. Nat Rev Clin Oncol 9: 268‐77 [PMID:22473102]
Chen Y et al. (2012) Eph receptors at synapses: implications in neurodegenerative diseases. Cell. Signal. 24: 606‐11 [PMID:22120527]
Fu HL et al. (2013) Discoidin domain receptors: unique receptor tyrosine kinases in collagen‐mediated signaling. J. Biol. Chem. 288: 7430‐7 [PMID:23335507]
Gherardi E et al. (2012) Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12: 89‐103 [PMID:22270953]
Goetz R et al. (2013) Exploring mechanisms of FGF signalling through the lens of structural biology. Nat. Rev. Mol. Cell Biol. 14: 166‐80 [PMID:23403721]
Guillemot F et al. (2011) From cradle to grave: the multiple roles of fibroblast growth factors in neural development. Neuron 71: 574‐88 [PMID:21867876]
Higashiyama S et al. (2011) Ectodomain shedding and remnant peptide signalling of EGFRs and their ligands. J. Biochem. 150: 15‐22 [PMID:21610047]
Ibáñez CF et al. (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci. 35: 431‐40 [PMID:22503537]
Koh GY. (2013) Orchestral actions of angiopoietin‐1 in vascular regeneration. Trends Mol Med 19: 31‐9 [PMID:23182855]
Larsen AK et al. (2011) Targeting EGFR and VEGF(R) pathway cross‐talk in tumor survival and angiogenesis. Pharmacol. Ther. 131: 80‐90 [PMID:21439312]
Lefebvre J et al. (2012) Met degradation: more than one stone to shoot a receptor down. FASEB J. 26: 1387‐99 [PMID:22223753]
Leitinger B. (2011) Transmembrane collagen receptors. Annu. Rev. Cell Dev. Biol. 27: 265‐90 [PMID:21568710]
Lennartsson J et al. (2012) Stem cell factor receptor/c‐Kit: from basic science to clinical implications. Physiol. Rev. 92: 1619‐49 [PMID:23073628]
Liang G et al. (2012) Anticancer molecules targeting fibroblast growth factor receptors. Trends Pharmacol. Sci. 33: 531‐41 [PMID:22884522]
Lisle JE et al. (2013) Eph receptors and their ligands: promising molecular biomarkers and therapeutic targets in prostate cancer. Biochim. Biophys. Acta 1835: 243‐57 [PMID:23396052]
Lu B et al. (2013) BDNF‐based synaptic repair as a disease‐modifying strategy for neurodegenerative diseases. Nat. Rev. Neurosci. 14: 401‐16 [PMID:23674053]
Morandi A et al. (2011) RET in breast cancer: functional and therapeutic implications. Trends Mol Med 17: 149‐57 [PMID:21251878]
Peters S et al. (2012) MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol 9: 314‐26 [PMID:22566105]
Roskoski Jr R. (2013) Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol. Res. 68: 68‐94 [PMID:23201355]
Sheffler‐Collins SI et al. (2012) EphBs: an integral link between synaptic function and synaptopathies. Trends Neurosci. 35: 293‐304 [PMID:22516618]
Shibuya M. (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem. 153: 13‐9 [PMID:23172303]
Turner CA et al. (2012) The fibroblast growth factor family: neuromodulation of affective behavior. Neuron 76: 160‐74 [PMID:23040813]
Woo KV et al. (2011) Role of Tie1 in shear stress and atherosclerosis. Trends Cardiovasc. Med. 21: 118‐23 [PMID:22681967]
Yamanashi Y et al. (2012) Activation of receptor protein‐tyrosine kinases from the cytoplasmic compartment. J. Biochem. 151: 353‐9 [PMID:22343747]
Type I RTKs: ErbB (epidermal growth factor) receptor family
Overview
ErbB family receptors are Class I receptor tyrosine kinases [62]. ERBB2 (also known as HER‐2 or NEU) appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand [63]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell‐surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed in many cancers, particularly forms of breast cancer.
Comments
[125I]EGF (human) has been used to label the ErbB1 EGF receptor. The extracellular domain of ErbB2 can be targetted by the antibodies trastuzumab and pertuzumab to inhibit ErbB family action. The intracellular ATP‐binding site of the tyrosine kinase domain can be inhibited by GW583340 (7.9‐8.0, [54]), gefitinib, erlotinib and tyrphostins AG879 and AG1478.
Type II RTKs: Insulin receptor family
Overview
The circulating peptide hormones insulin (INS, P01308) and the related insulin‐like growth factors (IGF) activate Class II receptor tyrosine kinases [62], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post‐translationally into two peptides, which then cross‐link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post‐translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889).
Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1‐5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.
| Nomenclature | Insulin receptor | Insulin‐like growth factor I receptor | Insulin receptor‐related receptor |
| Common abreviation | InsR | IGF1R | IRR |
| HGNC, UniProt | INSR, P06213 | IGF1R, P08069 | INSRR, P14616 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Inhibitors | – | BMS‐754807 (pIC50 8.7) [199], GSK‐1838705A (pIC50 8.7) [161], GSK‐1838705A (pK d 8.1) [38], PQ401 (pIC50>6) [50], AG 1024 (pIC50 4.7) [153] | – |
| Selective inhibitors | – | NVP‐AEW541 (pIC50 9.4) [53] | – |
| Endogenous agonists | insulin (INS, P01308) | insulin‐like growth factor 1 (IGF1, P05019), insulin‐like growth factor 2 (IGF2, P01344) | – |
Comments
There is evidence for low potency binding and activation of insulin receptors by IGF1. IGF2 also binds and activates the cation‐independent mannose 6‐phosphate receptor (also known as the insulin‐like growth factor II receptor), which lacks classical signalling capacity and appears to subserve a trafficking role [115]. INSRR, which has a much more discrete localization, being predominant in the kidney [95], currently lacks a cognate ligand or evidence for functional impact.
Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.
PQ401 inhibits the insulin‐like growth factor receptor [5], while BMS‐536924 inhibits both the insulin receptor and the insulin‐like growth factor receptor [198].
Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family
Overview
Type III RTKs include PDGFR, CSF‐1R (Ems), Kit and FLT3, which function as homo‐ or heterodimers. Endogenous ligands of PDGF receptors are homo‐ or heterodimeric: PDGFA, PDGFB, VEGFE and PDGFD (PDGFD, Q9GZP0) combine as homo‐ or heterodimers to activate homo‐ or heterodimeric PDGF receptors. SCF is a dimeric ligand for KIT. Ligands for CSF1R are either monomeric or dimeric glycoproteins, while the endogenous agonist for FLT3 is a homodimer.
| Nomenclature | platelet‐derived growth factor receptor, alpha polypeptide | platelet‐derived growth factor receptor, beta polypeptide | v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog | colony stimulating factor 1 receptor | fms‐related tyrosine kinase 3 |
| Common abreviation | PDGFRα | PDGFRβ | Kit | CSFR | FLT3 |
| HGNC, UniProt | PDGFRA, P16234 | PDGFRB, P09619 | KIT, P10721 | CSF1R, P07333 | FLT3, P36888 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Endogenous ligands | PDGF | PDGF | – | – | – |
| Endogenous ligands | – | – | stem cell factor (KITLG, P21583) | G‐CSF (CSF3, P09919), GM‐CSF (CSF2, P04141), M‐CSF (CSF1, P09603) | Fms‐related tyrosine kinase 3 ligand (FLT3LG, P49771) |
| Inhibitors | PP121 (pIC50 8.7) [7], crenolanib (pK d 8.7) [71], ENMD‐2076 (pIC50 7.2) [149] | crenolanib (pK d 8.5) [71], SU‐14813 (pIC50 8.4) [147], famitinib (pIC50 8.4) [24], sunitinib (pIC50 8.2) [91], sunitinib (pK i 8.1) [126] | sunitinib (pK d 9.4) [38], famitinib (pIC50 8.7) [24], masitinib (pK d 8.1) [38], SU‐14813 (pIC50 7.8) [147], AKN‐028 (pIC50 7.5) [46], sorafenib (pIC50 7.2) [196] | JNJ‐28312141 (pIC50 9.2) [116], Ki‐20227 (pK d 9.1) [38], Ki‐20227 (pIC50 8.7) [143], GW‐2580 (pK d 8.7) [38], JNJ‐28312141 (pK d 8.5) [38] | AC710 (pK d 9.3) [109], linifanib (pK d 9.2) [38], dovitinib (pK d 9.2) [38], crenolanib (pK d 9.1) [71], AST‐487 (pK d 9.1) [38], compound 8h [PMID: 22765894] (pIC50 9.1) [88], dovitinib (pIC50 8.5–9) [157, 183], ENMD‐2076 (pIC50 8.5) [149], tandutinib (pK d 8.5) [38], quizartinib (pIC50 8.4) [206], AKN‐028 (pIC50 8.2) [46], KW‐2449 (pIC50 8.2) [168], lestaurtinib (pK d 8.1) [38], midostaurin (pK d 8) [38], KW‐2449 (pK d 7.8) [38], sorafenib (pIC50 7.2) [196], AST‐487 (pK i 6.9) [193], tandutinib (pIC50 6.7) [86], AST‐487 (pIC50 6.3) [2], midostaurin (pIC50 6.3) [192] |
| Selective inhibitors | CP‐673451 (pIC50 8) [158] | CP‐673451 (pIC50 9) [158] | – | GW‐2580 (pIC50 7.2) [32] | G749 (pIC50 9.4) [99] |
| Comments | – | – | – | – | 5'‐fluoroindirubinoxime has been described as a selective FLT3 inhibitor [25]. |
Comments
Various small molecular inhibitors of type III RTKs have been described, including imatinib and nilotinib (targetting PDGFR, KIT and CSF1R); midostaurin and AC220 (quizartinib; FLT3), as well as pan‐type III RTK inhibitors such as sunitinib and sorafenib [148]; 5'‐fluoroindirubinoxime has been described as a selective FLT3 inhibitor [2].
Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family
Overview
VEGF receptors are homo‐ and heterodimeric proteins, which are characterized by seven Ig‐like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non‐signalling entity. Ligands at VEGF receptors are typically homodimeric. VEGFA (VEGFA, P15692) is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. VEGFB (VEGFB, P49765) and placental growth factor (PGF, P49763) activate VEGFR1 homodimers, while VEGFC (VEGFC, P49767) and VEGFD (FIGF, O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.
| Nomenclature | fms‐related tyrosine kinase 1 | kinase insert domain receptor | fms‐related tyrosine kinase 4 |
| Common abreviation | VEGFR‐1 | VEGFR‐2 | VEGFR‐3 |
| HGNC, UniProt | FLT1, P17948 | KDR, P35968 | FLT4, P35916 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Endogenous ligands | VEGFA (VEGFA, P15692), VEGFB (VEGFB, P49765) | VEGFA (VEGFA, P15692), VEGFC (VEGFC, P49767), VEGFE (PDGFC, Q9NRA1) | VEGFC (VEGFC, P49767), VEGFD (FIGF, O43915), VEGFE (PDGFC, Q9NRA1) |
| Inhibitors | SU‐14813 (pIC50 8.7) [147], CEP‐11981 (pIC50 8.5) [77], semaxanib (pIC50 8.1) [15] | axitinib (pIC50 9.6) [100], cabozantinib (pIC50 9.5) [203], foretinib (pIC50 8.2–9.1) [137], cediranib (pK d 9) [38], XL‐647 (pIC50 8.8) [57], compound 13a [PMID: 23639540] (pIC50 8.8) [45], SU‐14813 (pK d 8.6) [38], motesanib (pK d 8.6) [38], famitinib (pIC50 8.3) [24], axitinib (pK d 8.2) [38], PLX‐4720 (pK i 8.1) [126], CP‐547632 (pIC50 8) [11], PP121 (pIC50 7.9) [7], golvatinib (pIC50 7.8) [139], brivanib (pIC50 7.6) [13], ENMD‐2076 (pIC50 7.4) [149], BMS‐690514 (pIC50 7.3) [117], SU‐14813 (pIC50 7.3) [147], sorafenib (pK d 7.2) [38], vatalanib (pK d 7.2) [38], sorafenib (pIC50 7.1) [196] | XL‐647 (pIC50 8.1) [57], sunitinib (pIC50 8.1) [87], nintedanib (pIC50 7.9) [74] |
| (Sub)family‐selective inhibitors | pazopanib (pIC50 8) [68] | pazopanib (pK d 7.8) [38], pazopanib (pIC50 7.5) [68] | pazopanib (pIC50 7.3) [68] |
| Antibodies | – | ramucirumab (Antagonist) (pIC50 9) [113] | – |
Comments
The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [49], Ki8751 [94] and ZM323881, a novel inhibitor of vascular endothelial growth factor‐receptor‐2 tyrosine kinase activity [195] are described as VEGFR2‐selective tyrosine kinase inhibitors. Bevacizumab is a monoclonal antibody directed against VEGF‐A, used clinically for the treatment of certain metastatic cancers; an antibody fragment has been used for wet age‐related macular degeneration.
Type V RTKs: FGF (fibroblast growth factor) receptor family
Overview
Fibroblast growth factor (FGF) family receptors act as homo‐ and heterodimers, and are characterized by Ig‐like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone‐like FGFs. FGF1‐FGF10 have been identified to act through FGF receptors, while FGF11‐14 appear to signal through intracellular targets. Other family members are less well characterized [194].
Comments
Splice variation of the receptors can influence agonist responses. FGFRL1 (Q8N441) is a truncated kinase‐null analogue.
Various antibodies and tyrosine kinase inhibitors have been developed against FGF receptors [107, 210]. PD161570 is an FGFR tyrosine kinase inhibitor [10], while PD173074 has been described to inhibit FGFR1 and FGFR3 [169].
Type VI RTKs: PTK7/CCK4
Overview
The PTK7 receptor is associated with polarization of epithelial cells and the development of neural structures. Sequence analysis suggests that the gene product is catalytically inactive as a protein kinase, although there is evidence for a role in Wnt signalling [152].
| Nomenclature | protein tyrosine kinase 7 (inactive) |
| Common abreviation | CCK4 |
| HGNC, UniProt | PTK7, Q13308 |
| EC number | 2.7.10.1 |
Comments
Thus far, no selective PTK7 inhibitors have been described.
Type VII RTKs: Neurotrophin receptor/Trk family
Overview
The neurotrophin receptor family of RTKs include trkA, trkB and trkC (tropomyosin‐related kinase) receptors, which respond to NGF, BDNF and neurotrophin‐3, respectively. They are associated primarily with proliferative and migration effects in neural systems. Various isoforms of neurotrophin receptors exist, including truncated forms of trkB and trkC, which lack catalytic domains. p75(TNFRSF16, also known as nerve growth factor receptor), which has homologies with tumour necrosis factor receptors, lacks a tyrosine kinase domain, but can signal via ceramide release and nuclear factor κB (NF‐κB) activation. Both trkA and trkB contain two leucine‐rich regions and can exist in monomeric or dimeric forms.
| Nomenclature | neurotrophic tyrosine kinase, receptor, type 1 | neurotrophic tyrosine kinase, receptor, type 2 | neurotrophic tyrosine kinase, receptor, type 3 |
| Common abreviation | trkA | trkB | trkC |
| HGNC, UniProt | NTRK1, P04629 | NTRK2, Q16620 | NTRK3, Q16288 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Endogenous ligands | NGF (NGF, P01138) >neurotrophin‐3 (NTF3, P20783) | BDNF (BDNF, P23560), neurotrophin‐4 (NTF4, P34130) >neurotrophin‐3 (NTF3, P20783) | – |
| Endogenous ligands | – | – | neurotrophin‐3 (NTF3, P20783) |
| Inhibitors | compound 2c [PMID: 24900538] (pIC50 8.9) [189], milciclib (pIC50 7.3) [17] | – | – |
| (Sub)family‐selective inhibitors | AZD1332 (pIC50>8.3) 9, GNF‐5837 (pIC50 8) [5] | AZD1332 (pIC50>8.3) 9, GNF‐5837 (pIC50 8.1) [5] | AZD1332 (pIC50>8.3) 9, GNF‐5837 (pIC50 8.1) [5] |
Comments
[125I]NGF (human) and [125I]BDNF (human) have been used to label the trkA and trkB receptor, respectively. p75 influences the binding of NGF (NGF, P01138) and neurotrophin‐3 (NTF3, P20783) to trkA. The ligand selectivity of p75 appears to be dependent on the cell type; for example, in sympathetic neurones, it binds neurotrophin‐3 (NTF3, P20783) with comparable affinity to trkC [40].
Small molecule agonists of trkB have been described, including LM22A4 [123], while ANA12 has been described as a non‐competitive antagonist of BDNF binding to trkB [23]. GNF5837 is a family‐selective tyrosine kinase inhibitor [4], while the tyrosine kinase activity of the trkA receptor can be inhibited by GW441756 (pIC50= 8.7, [200]) and tyrphostin AG879 [142].
Type VIII RTKs: ROR family
Overview
Members of the ROR family appear to be activated by ligands complexing with other cell‐surface proteins. Thus, ROR1 and ROR2 appear to be activated by Wnt‐5a (WNT5A, P41221) binding to a Frizzled receptor thereby forming a cell‐surface multiprotein complex [64].
| Nomenclature | receptor tyrosine kinase‐like orphan receptor 1 | receptor tyrosine kinase‐like orphan receptor 2 |
| Common abreviation | ROR1 | ROR2 |
| HGNC, UniProt | ROR1, Q01973 | ROR2, Q01974 |
| EC number | 2.7.10.1 | 2.7.10.1 |
Type IX RTKs: MuSK
Overview
The muscle‐specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. Agrin (AGRN, O00468) forms a complex with low‐density lipoprotein receptor‐related protein 4 (LRP4, O75096) to activate MuSK [89].
| Nomenclature | muscle, skeletal, receptor tyrosine kinase |
| Common abreviation | MuSK |
| HGNC, UniProt | MUSK, O15146 |
| EC number | 2.7.10.1 |
Comments
Thus far, no selective MuSK inhibitors have been described.
Type X RTKs: HGF (hepatocyte growth factor) receptor family
Overview
HGF receptors regulate maturation of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post‐translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by HGF‐inhibitor 1 (SPINT1, O43278), a serine protease inhibitor. MST1, the ligand of RON, is two disulphide‐linked peptide chains generated by proteolysis of a single gene product.
| Nomenclature | MET proto‐oncogene, receptor tyrosine kinase | macrophage stimulating 1 receptor |
| Common abreviation | MET | Ron |
| HGNC, UniProt | MET, P08581 | MST1R, Q04912 |
| EC number | 2.7.10.1 | 2.7.10.1 |
| Endogenous ligands | hepatocyte growth factor (HGF, P14210) | macrophage stimulating protein 1 (MST1, P09603) |
| Inhibitors | capmatinib (pIC50 9.9) [112], SGX‐523 (pK d 9.7) [38], PHA‐665752 (pK d 9.6) [38], foretinib (pIC50 9.3–9.4) [106, 137], cabozantinib (pIC50 8.9) [203], foretinib (pK d 8.9) [38], MK‐2461 (pIC50 8.6) [146], BMS‐777607 (pIC50 8.4) [164], PHA‐665752 (pK i 8.4) [26], SU11274 (pIC50 8) [190], golvatinib (pIC50 7.8) [139], tivantinib (pK i 6.4) [135] | BMS‐777607 (pIC50 8.7) [164] |
| Selective inhibitors | SGX‐523 (pIC50 8.4) [19] | – |
Comments
PF04217903 is a selective Met tyrosine kinase inhibitor [34].SU11274 is an inhibitor of the HGF receptor [162], with the possibility of further targets [8].
Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family
Overview
Members of this RTK family represented a novel structural motif, when sequenced. The ligands for this family, growth arrest specific protein 6 (GAS6, Q14393) and protein S (PROS1, P07225), are secreted plasma proteins which undergo vitamin K‐dependent post‐translational modifications generating carboxyglutamate‐rich domains which are able to bind to negatively‐charged surfaces of apoptotic cells.
| Nomenclature | AXL receptor tyrosine kinase | TYRO3 protein tyrosine kinase | MER proto‐oncogene, tyrosine kinase |
| Common abreviation | Axl | Tyro3 | Mer |
| HGNC, UniProt | AXL, P30530 | TYRO3, Q06418 | MERTK, Q12866 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Endogenous ligands | growth arrest specific protein 6 (GAS6, Q14393) [138], protein S (PROS1, P07225) [172] | growth arrest specific protein 6 (GAS6, Q14393) [138], protein S (PROS1, P07225) [172] | growth arrest specific protein 6 (GAS6, Q14393) [138] |
Comments
AXL tyrosine kinase inhibitors have been described [130].
Type XII RTKs: TIE family of angiopoietin receptors
Overview
The TIE family were initially associated with formation of blood vessels. Endogenous ligands are angiopoietin‐1 (ANGPT1, Q15389), angiopoietin‐2 (ANGPT2, O15123), and angiopoietin‐4 (ANGPT4, Q9Y264). Angiopoietin‐2 (ANGPT2, O15123) appears to act as an endogenous antagonist of angiopoietin‐1 function.
| Nomenclature | tyrosine kinase with immunoglobulin‐like and EGF‐like domains 1 | TEK tyrosine kinase, endothelial |
| Common abreviation | TIE1 | TIE2 |
| HGNC, UniProt | TIE1, P35590 | TEK, Q02763 |
| EC number | 2.7.10.1 | 2.7.10.1 |
| Endogenous ligands | – | angiopoietin‐1 (ANGPT1, Q15389), angiopoietin‐4 (ANGPT4, Q9Y264) |
Type XIII RTKs: Ephrin receptor family
Overview
Ephrin receptors are a family of 15 RTKs (the largest family of RTKs) with two identified subfamilies (EphA and EphB), which have a role in the regulation of neuronal development, cell migration, patterning and angiogenesis. Their ligands are membrane‐associated proteins, thought to be glycosylphosphatidylinositol‐linked for EphA (ephrin‐A1 (EFNA1, P20827) , ephrin‐A2 (EFNA2, O43921), ephrin‐A3 (EFNA3, P52797), ephrin‐A4 (EFNA4, P52798) and ephrin‐A5 (EFNA5, P52803)) and 1TM proteins for Ephrin B (ENSFM00250000002014: ephrin‐B1 (EFNB1, P98172), ephrin‐B2 (EFNB2, P52799) and ephrin‐B3 (EFNB3, Q15768)), although the relationship between ligands and receptors has been incompletely defined.
| Nomenclature | EPH receptor A1 | EPH receptor A2 | EPH receptor A3 | EPH receptor A4 | EPH receptor A5 | EPH receptor A6 | EPH receptor A7 |
| Common abreviation | EphA1 | EphA2 | EphA3 | EphA4 | EphA5 | EphA6 | EphA7 |
| HGNC, UniProt | EPHA1, P21709 | EPHA2, P29317 | EPHA3, P29320 | EPHA4, P54764 | EPHA5, P54756 | EPHA6, Q9UF33 | EPHA7, Q15375 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Inhibitors | compound 20[PMID: 23489211] (pIC50 5.6) [79] | – | – | – | – | – | – |
| Nomenclature | EPH receptor A8 | EPH receptor A10 | EPH receptor B1 | EPH receptor B2 | EPH receptor B3 | EPH receptor B4 | EPH receptor B6 |
| Common abreviation | EphA8 | EphA10 | EphB1 | EphB2 | EphB3 | EphB4 | EphB6 |
| HGNC, UniProt | EPHA8, P29322 | EPHA10, Q5JZY3 | EPHB1, P54762 | EPHB2, P29323 | EPHB3, P54753 | EPHB4, P54760 | EPHB6, O15197 |
| EC number | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 | 2.7.10.1 |
| Inhibitors | – | – | compound 66[PMID: 19788238] (pIC50 9) [97] | – | – | XL‐647 (pIC50 8.9) [57] | – |
Type XIV RTKs: RET
Overview
Ret proto‐oncogene (Rearranged during transfection) is a transmembrane tyrosine kinase enzyme which is employed as a signalling partner for members of the GDNF family receptors. Ligand‐activated GFR appears to recruit Ret as a dimer, leading to activation of further intracellular signalling pathways. Ret appears to be involved in neural crest development, while mutations may be involved in multiple endocrine neoplasia, Hirschsprung's disease, and medullary thyroid carcinoma.
| Nomenclature | ret proto‐oncogene |
| Common abreviation | Ret |
| HGNC, UniProt | RET, P07949 |
| EC number | 2.7.10.1 |
| Inhibitors | tamatinib (pIC50 8.3) [27], vandetanib (pK d 7.5) [38], vandetanib (pIC50 7) [22] |
Comments
A number of tyrosine kinase inhibitors targeting RET have been described [47].
Type XV RTKs: RYK
Overview
The ‘related to tyrosine kinase receptor’ (Ryk) is structurally atypical of the family of RTKs, particularly in the activation and ATP‐binding domains. RYK has been suggested to lack kinase activity and appears to be involved, with FZD8, in the Wnt signalling system [152].
| Nomenclature | receptor‐like tyrosine kinase |
| Common abreviation | RYK |
| HGNC, UniProt | RYK, P34925 |
| EC number | 2.7.10.1 |
Comments
Thus far, no selective RYK inhibitors have been described.
Type XVI RTKs: DDR (collagen receptor) family
Overview
Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are structurally‐related membrane protein tyrosine kinases activated by collagen. Collagen is probably the most abundant protein in man, with at least 29 families of genes encoding proteins, which undergo splice variation and post‐translational processing, and may exist in monomeric or polymeric forms, producing a triple‐stranded, twine‐like structure. In man, principal family members include COL1A1 (COL1A1, P02452), COL2A1 (COL2A1, P02458), COL3A1 (COL3A1, P02461) and COL4A1 (COL4A1, P02462).
| Nomenclature | discoidin domain receptor tyrosine kinase 1 | discoidin domain receptor tyrosine kinase 2 |
| Common abreviation | DDR1 | DDR2 |
| HGNC, UniProt | DDR1, Q08345 | DDR2, Q16832 |
| EC number | 2.7.10.1 | 2.7.10.1 |
| Inhibitors | compound 7k [PMID: 23521020] (pIC50 8.6) [51] | – |
Comments
The tyrosine kinase inhibitors of DDR, imatinib and nilotinib, were identified from proteomic analysis [39]. Other collagen receptors include glycoprotein VI (Q9HCN6), leukocyte‐associated immunoglobulin‐like receptor 1 (Q6GTX8), leukocyte‐associated immunoglobulin‐like receptor 2 (Q6ISS4) and osteoclast‐associated immunoglobulin‐like receptor (Q8IYS5).
Type XVII RTKs: ROS receptors
| Nomenclature | c‐ros oncogene 1, receptor tyrosine kinase |
| Common abreviation | ROS |
| HGNC, UniProt | ROS1, P08922 |
| EC number | 2.7.10.1 |
Comments
crizotinib is a tyrosine kinase inhibitor, anti‐cancer drug targeting ALK and ROS1.
Type XVIII RTKs: LMR family
Overview
The LMR kinases are unusual amongst the RTKs in possessing a short extracellular domain and extended intracellular domain (hence the ‘Lemur’ name reflecting the long tail). A precise function for these receptors has yet to be defined, although LMR1 was identified as a potential marker of apoptosis [52], giving rise to the name AATYK (Apoptosis‐associated tyrosine kinase); while over‐expression induces differentiation in neuroblastoma cells [156].
| Nomenclature | apoptosis‐associated tyrosine kinase | lemur tyrosine kinase 2 | lemur tyrosine kinase 3 |
| Common abreviation | Lmr1 | Lmr2 | Lmr3 |
| HGNC, UniProt | AATK, Q6ZMQ8 | LMTK2, Q8IWU2 | LMTK3, Q96Q04 |
| EC number | 2.7.11.1 | 2.7.11.1 | 2.7.11.1 |
Comments
As yet no selective inhibitors of the LMR family have been described.
Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family
Overview
The LTK family appear to lack endogenous ligands. LTK is subject to tissue‐specific splice variation, which appears to generate products in distinct subcellular locations. ALK fusions created by gene translocations and rearrangements are associated with many types of cancer, including large cell lymphomas, inflammatory myofibrilastic tumours and non‐small cell lung cancer [120].
| Nomenclature | leukocyte receptor tyrosine kinase | anaplastic lymphoma receptor tyrosine kinase |
| Common abreviation | LTK | ALK |
| HGNC, UniProt | LTK, P29376 | ALK, Q9UM73 |
| EC number | 2.7.10.1 | 2.7.10.1 |
| Inhibitors | – | GSK‐1838705A (pIC50 9.3) [161], compound 8e [PMID: 24432909] (pIC50 9.1) [76], crizotinib (pIC50 9) [35], NVP‐TAE684 (pK d 9) [38], compound 25b [PMID: 22564207] (pIC50 8.7) [59] |
| Selective inhibitors | – | ceritinib (pIC50 9.7) [120] |
| Comments | – | crizotinib appears to be a selective ALK inhibitor acting on the tyrosine kinase activity [58] |
Type XX RTKs: STYK1
Overview
Similar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. STYK1 (also known as Novel Oncogene with Kinase‐domain, NOK) has been suggested to co‐localize with activated EGF receptor [43].
| Nomenclature | serine/threonine/tyrosine kinase 1 |
| Common abreviation | STYK1 |
| HGNC, UniProt | STYK1, Q6J9G0 |
| EC number | 2.7.10.2 |
Comments
As yet, no selective inhibitors of STYK1 have been described.
Receptor tyrosine phosphatases (RTP)
Overview
Receptor tyrosine phosphatases (RTP) are cell‐surface proteins with a single TM region and intracellular phosphotyrosine phosphatase activity. Many family members exhibit constitutive activity in heterologous expression, dephosphorylating intracellular targets such as Src tyrosine kinase (SRC) to activate signalling cascades. Family members bind components of the extracellular matrix or cell‐surface proteins indicating a role in intercellular communication. Listed here are those family members with putative endogenous ligands.
| Nomenclature | RTP Type C | RTP Type D | RTP Type F | RTP Type G |
| HGNC, UniProt | PTPRC, P08575 | PTPRD, P23468 | PTPRF, P10586 | PTPRG, P23470 |
| Putative endogenous ligands | galectin‐1 (LGALS1, P09382) [188] | netrin‐G3 ligand (LRRC4B, Q9NT99) [96] | netrin‐G3 ligand (LRRC4B, Q9NT99) [96] | contactin‐3 (CNTN3, Q9P232), contactin‐4 (CNTN4, Q8IWV2), contactin‐5 (CNTN5, O94779), contactin‐6 (CNTN6, Q9UQ52) [16] |
| Nomenclature | RTP Type K | RTP Type S | RTP Type Z1 |
| HGNC, UniProt | PTPRK, Q15262 | PTPRS, Q13332 | PTPRZ1, P23471 |
| Putative endogenous ligands | galectin‐3 (LGALS3, P17931), galectin‐3 binding protein (LGALS3BP, Q08380) [90] | chondroitin sulphate proteoglycan 3 (NCAN, O14594), netrin‐G3 ligand (LRRC4B, Q9NT99) [96, 166] | contactin‐1 (CNTN1, Q12860), pleiotrophin (PTN, C9JR52) (acts as a negative regulator) [16, 127] |
Further Reading
Böhmer F et al. (2013) Protein tyrosine phosphatase structure‐function relationships in regulation and pathogenesis. FEBS J. 280: 413‐31 [PMID:22682070]
Dushek O et al. (2012) Non‐catalytic tyrosine‐phosphorylated receptors. Immunol. Rev. 250: 258‐76 [PMID:23046135]
He R et al. (2013) Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J. 280: 731‐50 [PMID:22816879]
Julien SG et al. (2011) Inside the human cancer tyrosine phosphatome. Nat. Rev. Cancer 11: 35‐49 [PMID:21179176]
Mohebiany AN et al. (2013) Receptor‐type tyrosine phosphatase ligands: looking for the needle in the haystack. FEBS J. 280: 388‐400 [PMID:22682003]
Sastry SK et al. (2011) Checks and balances: interplay of RTKs and PTPs in cancer progression. Biochem. Pharmacol. 82: 435‐40 [PMID:21704606]
Tumour necrosis factor (TNF) receptor family
Overview
The TNF receptor superfamily (TNFRSF, provisional nomenclature) displays limited homology beyond an extracellular domain rich in cysteine residues and is activated by at least 18 different human homologues of TNF referred to as the TNF superfamily (TNFSF). Some homologues lacking transmembrane and cytoplasmic domains function as decoy receptors binding ligand without inducing cell signalling. Many of these receptors and ligands function as multimeric entities. Signalling through these receptors is complex and involves interaction with cytoplasmic adaptor proteins (such as TRADD and TRAF1). Several of these receptors contain cytoplasmic motifs known as ‘death domains’, which upon activation serve to recruit death domain‐ and death effector domain‐containing proteins crucial for the initiation of an apoptotic response. Additional signalling pathways include the regulation of the nuclear factor κB or mitogen‐activated protein kinase pathways. Pharmacological manipulation of these receptors is mainly enacted through chelating the endogenous agonists with humanised monoclonal antibodies (e.g. Infliximab or adalimumab) or recombinant fusion proteins of IgG and soluble receptors (e.g. etanercept). Some mutated forms of TNF ligands are capable of selecting for different receptor subtypes.
| Nomenclature | tumor necrosis factor receptor 1 | tumor necrosis factor receptor 2 | lymphotoxin β receptor | OX40 | CD40 |
| Systematic nomenclature | TNFRSF1A | TNFRSF1B | TNFRSF3 | TNFRSF4 | TNFRSF5 |
| Common abreviation | TNFR1 | TNFR2 | – | – | – |
| HGNC, UniProt | TNFRSF1A, P19438 | TNFRSF1B, P20333 | LTBR, P36941 | TNFRSF4, P43489 | CD40, P25942 |
| Adaptor proteins | TRADD | TRAF1, TRAF2, TRAF5 | TRAF3, TRAF4, TRAF5 | TRAF1, TRAF2, TRAF3, TRAF5 | TRAF1, TRAF2, TRAF3, TRAF5, TRAF6 |
| Endogenous ligands | lymphotoxin‐α (LTA, P01374), tumour necrosis factormembrane form (TNF, P01375), tumour necrosis factorshed form (TNF, P01375) | lymphotoxin‐α (LTA, P01374), tumour necrosis factormembrane form (TNF, P01375) | LIGHT (TNFSF14, O43557), lymphotoxin β2α1 heterotrimer (LTA LTB, P01374 Q06643) | OX‐40 ligand (TNFSF4, P23510) | CD40 ligand (CD40LG, P29965) |
| Nomenclature | Fas | decoy receptor 3 | CD27 | CD30 | 4‐1BB |
| Systematic nomenclature | TNFRSF6 | TNFRSF6B | TNFRSF7 | TNFRSF8 | TNFRSF9 |
| HGNC, UniProt | FAS, P25445 | TNFRSF6B, O95407 | CD27, P26842 | TNFRSF8, P28908 | TNFRSF9, Q07011 |
| Adaptor proteins | FADD | – | TRAF2, SIVA | TRAF1, TRAF2, TRAF3, TRAF5 | TRAF1, TRAF2, TRAF3 |
| Endogenous ligands | Fas ligand (FASLG, P48023) | – | CD70 (CD70, P32970) | CD30 ligand (TNFSF8, P32971) | 4‐1BB ligand (TNFSF9, P41273) |
| Antibodies | – | – | – | brentuximab vedotin (Inhibition) | – |
| Comments | – | Decoy receptor for LIGHT (TNFSF14, O43557), TL1A (TNFSF15, O95150) and Fas ligand (FASLG, P48023). | – | – | – |
| Nomenclature | death receptor 4 | death receptor 5 | decoy receptor 1 | decoy receptor 2 | receptor activator of NF‐kappa B |
| Systematic nomenclature | TNFRSF10A | TNFRSF10B | TNFRSF10C | TNFRSF10D | TNFRSF11A |
| Common abreviation | DR4 | DR5 | – | – | RANK |
| HGNC, UniProt | TNFRSF10A, O00220 | TNFRSF10B, O14763 | TNFRSF10C, O14798 | TNFRSF10D, Q9UBN6 | TNFRSF11A, Q9Y6Q6 |
| Adaptor proteins | FADD | FADD | – | – | TRAF1, TRAF2, TRAF3, TRAF5, TRAF6 |
| Endogenous ligands | TRAIL (TNFSF10, P50591) | TRAIL (TNFSF10, P50591) | – | – | RANK ligand (TNFSF11, O14788) |
| Comments | – | – | Decoy receptor for TRAIL (TNFSF10, P50591). | Decoy receptor for TRAIL (TNFSF10, P50591). | – |
| Nomenclature | osteoprotegerin | death receptor 3 | TWEAK receptor | TACI |
| Systematic nomenclature | TNFRSF11B | TNFRSF25 | TNFRSF12A | TNFRSF13B |
| Common abreviation | OPG | DR3 | – | – |
| HGNC, UniProt | TNFRSF11B, O00300 | TNFRSF25, Q93038 | TNFRSF12A, Q9NP84 | TNFRSF13B, O14836 |
| Adaptor proteins | – | TRADD | TRAF1, TRAF2, TRAF3 | TRAF2, TRAF5, TRAF6 |
| Endogenous ligands | – | TL1A (TNFSF15, O95150) | TWEAK (TNFSF12, O43508) | APRIL (TNFSF13, O75888), BAFF (TNFSF13B, Q9Y275) |
| Comments | Acts as a decoy receptor for RANK ligand (TNFSF11, O14788) and possibly for TRAIL (TNFSF10, P50591). | – | – | – |
| Nomenclature | BAFF receptor | herpes virus entry mediator | nerve growth factor receptor | B cell maturation antigen |
| Systematic nomenclature | TNFRSF13C | TNFRSF14 | TNFRSF16 | TNFRSF17 |
| Common abreviation | BAFF‐R | HVEM | – | BCMA |
| HGNC, UniProt | TNFRSF13C, Q96RJ3 | TNFRSF14, Q92956 | NGFR, P08138 | TNFRSF17, Q02223 |
| Adaptor proteins | TRAF3 | TRAF2, TRAF3, TRAF5 | TRAF2, TRAF4, TRAF6 | TRAF1, TRAF2, TRAF3, TRAF5, TRAF6 |
| Endogenous ligands | BAFF (TNFSF13B, Q9Y275) | B and T lymphocyte attenuator (BTLA, Q7Z6A9), LIGHT (TNFSF14, O43557), lymphotoxin‐α (LTA, P01374) | BDNF (BDNF, P23560), NGF (NGF, P01138), neurotrophin‐3 (NTF3, P20783), neurotrophin‐4 (NTF4, P34130) | APRIL (TNFSF13, O75888), BAFF (TNFSF13B, Q9Y275) |
| Nomenclature | glucocorticoid‐induced TNF receptor | toxicity and JNK inducer | RELT | death receptor 6 |
| Systematic nomenclature | TNFRSF18 | TNFRSF19 | TNFRSF19L | TNFRSF21 |
| Common abreviation | GITR | TAJ | – | DR6 |
| HGNC, UniProt | TNFRSF18, Q9Y5U5 | TNFRSF19, Q9NS68 | RELT, Q969Z4 | TNFRSF21, O75509 |
| Adaptor proteins | TRAF1, TRAF2, TRAF3, SIVA | TRAF1, TRAF2, TRAF3, TRAF5 | TRAF1 | TRADD |
| Endogenous ligands | TL6 (TNFSF18, Q9UNG2) | lymphotoxin‐α (LTA, P01374) | – | – |
| Nomenclature | TNFRSF22 | TNFRSF23 | ectodysplasin A2 isoform receptor | ectodysplasin 1, anhidrotic receptor |
| Systematic nomenclature | – | – | TNFRS27 | – |
| HGNC, UniProt | – | – | EDA2R, Q9HAV5 | EDAR, Q9UNE0 |
| Adaptor proteins | – | – | TRAF1, TRAF3, TRAF6 | TRAF1, TRAF2, TRAF3 |
| Endogenous ligands | – | – | ectodysplasin A2 (EDA, Q92838) [204] | ectodysplasin A1 (EDA, Q92838) [204] |
Comments
TNFRSF1A is preferentially activated by the shed form of TNF ligand, whereas the membrane‐bound form of TNF serves to activate TNFRSF1A and TNFRSF1B equally. The neurotrophins nerve growth factor (NGF (NGF, P01138)), brain‐derived neurotrophic factor (BDNF (BDNF, P23560)), neurotrophin‐3 (NTF3, P20783) (NTF3) and neurotrophin‐4 (NTF4, P34130) (NTF4) are structurally unrelated to the TNF ligand superfamily but exert some of their actions through the “low affinity nerve growth factor receptor” (NGFR (TNFRSF16)) as well as through the TRK family of receptor tyrosine kinases. The endogenous ligands for EDAR and EDA2R are, respectively, the membrane (Q92838[1‐391]) and secreted (Q92838[160‐391]) isoforms of Ectodysplasin‐A (EDA, Q92838).
Further Reading
Aggarwal BB. (2003) Signalling pathways of the TNF superfamily: a double‐edged sword. Nat. Rev. Immunol. 3: 745‐56 [PMID:12949498]
Ashkenazi A. (2002) Targeting death and decoy receptors of the tumour‐necrosis factor superfamily. Nat. Rev. Cancer 2: 420‐30 [PMID:12189384]
Mahmood Z et al. (2010) Death receptors: targets for cancer therapy. Exp. Cell Res. 316: 887‐99 [PMID:20026107]
Rickert RC et al. (2011) Signaling by the tumor necrosis factor receptor superfamily in B‐cell biology and disease. Immunol. Rev. 244: 115‐33 [PMID:22017435]
Tansey MG et al. (2009) The TNF superfamily in 2009: new pathways, new indications, and new drugs. Drug Discov. Today 14: 1082‐8 [PMID:19837186]
Alexander, S. PH. , Fabbro, D. , Kelly, E. , Marrion, N. , Peters, J. A. , Benson, H. E. , Faccenda, E. , Pawson, A. J. , Sharman, J. L. , Southan, C. , Davies, J. A. , and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Catalytic receptors. British Journal of Pharmacology, 172: 5979–6023. doi: 10.1111/bph.13353.
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