Literature DB >> 29055036

THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Catalytic receptors.

Stephen Ph Alexander1, Doriano Fabbro2, Eamonn Kelly3, Neil V Marrion3, John A Peters4, Elena Faccenda5, Simon D Harding5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5.   

Abstract

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), 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. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13876/full. Catalytic 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 landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
© 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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Year:  2017        PMID： 29055036      PMCID： PMC5650661          DOI： 10.1111/bph.13876

Source DB:  PubMed          Journal:  Br J Pharmacol        ISSN： 0007-1188            Impact factor:   8.739


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 further group of catalytic receptors for the Guide is the integrins, which have roles in cell:cell communication, often associated with signaling in the blood.

Family structure

S226 Cytokine receptor family S227 IL‐2 receptor family S228 IL‐3 receptor family S229 IL‐6 receptor family S231 IL‐12 receptor family S232 Prolactin receptor family S232 Interferon receptor family S233 IL‐10 receptor family S234 Immunoglobulin‐like family of IL‐1 receptors S235 IL‐17 receptor family S236 GDNF receptor family S237 Integrins S241 Natriuretic peptide receptor family S242 Pattern recognition receptors S242 Toll‐like receptor family S244 NOD‐like receptor family Ű RIG‐I‐like receptor family Ű Receptor kinases Ű TK: Tyrosine kinase S246 Receptor tyrosine kinases (RTKs) S246 Type I RTKs: ErbB (epidermal growth factor) receptor family S247 Type II RTKs: Insulin receptor family S248 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family S250 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family S250 Type V RTKs: FGF (fibroblast growth factor) receptor family S251 Type VI RTKs: PTK7/CCK4 S252 Type VII RTKs: Neurotrophin receptor/Trk family S253 Type VIII RTKs: ROR family S253 Type IX RTKs: MuSK S254 Type X RTKs: HGF (hepatocyte growth factor) receptor family S255 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family S255 Type XII RTKs: TIE family of angiopoietin receptors S256 Type XIII RTKs: Ephrin receptor family S256 Type XIV RTKs: RET S257 Type XV RTKs: RYK S258 Type XVI RTKs: DDR (collagen receptor) family S258 Type XVII RTKs: ROS receptors S258 Type XVIII RTKs: LMR family S259 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family S260 Type XX RTKs: STYK1 Ű TKL: Tyrosine kinase‐like S260 Receptor serine/threonine kinase (RSTK) fam‐ily S261 Type I receptor serine/threonine kinases S261 Type II receptor serine/threonine kinases S262 Type III receptor serine/threonine kinases S262 RSTK functional heteromers S264 Receptor tyrosine phosphatase (RTP) family S265 Tumour necrosis factor (TNF) 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‐ 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. 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.

IL‐2 receptor family

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 [204].

IL‐3 receptor family

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.

Subunits

IL‐6 receptor family

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.

Further reading on IL‐6 receptor family

Ho, LJ et al. (2015) Biological effects of interleukin‐6: Clinical applications in autoimmune diseases and cancers. Biochem Pharmacol 97: 16‐26 [PMID:26080005] Rothaug, M et al. (2016) The role of interleukin‐6 signaling in nervous tissue. Biochim Biophys Acta 1863: 1218‐27 [PMID:27016501]

IL‐12 receptor family

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.

Prolactin receptor family

Prolactin family receptors form homodimers in the presence of their respective ligands, associate exclusively with Jak2 and signal via Stat5.

Further reading on Prolactin receptor family

Cabrera‐Reyes, EA et al. (2017) Prolactin function and putative expression in the brain. Endocrine [PMID:28634745] Goffin, V. (2017) Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge. Pharmacol Ther [PMID:28549597]

Interferon receptor family

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).

Further reading on Interferon receptor family

Kotenko, SV et al. (2017) Contribution of type III interferons to antiviral immunity: location, location, location. J Biol Chem 292: 7295‐7303 [PMID:28289095] Ng, CT, et al. (2016) Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes. Cell 164: 349‐52 [PMID:26824652] Schreiber, G. (2017) The molecular basis for differential type I interferon signaling. J Biol Chem 292: 7285‐7294 [PMID:28289098]

IL‐10 receptor family

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; IFNLR1(previouly known as IL28RA)/IL10RB responds to IFN‐λ1, ‐λ2 and ‐λ3 (previouly known as IL‐29, IL‐28A and IL‐28B respectively).

Further reading on IL‐10 receptor family

Felix J et al. (2017) Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat. Rev. Immunol. 17: 112‐129 [PMID:28028310]

Immunoglobulin‐like family of IL‐1 receptors

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.

IL‐17 receptor family

: The IL17 cytokine family consists of six ligands (IL‐17A‐F), which signal through five receptors (IL‐17RA‐E).

Further reading on IL‐17 receptor family

Beringer, A et al. (2016) IL‐17 in Chronic Inflammation: From Discovery to Targeting. Trends Mol Med 22: 230‐41 [PMID:26837266] Lubberts, E. (2015) The IL‐23‐IL‐17 axis in inflammatory arthritis. Nat Rev Rheumatol 11: 415‐29 [PMID:25907700]

GDNF receptor family

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).

Comments

Inhibitors of other receptor tyrosine kinases, such as semaxanib, which inhibits VEGF receptor function, may also inhibit Ret function [132]. 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 on GDNF receptor family

Allen SJ et al. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138: 155‐75 [PMID:23348013] Ibanez CF et al. (2017) Biology of GDNF and its receptors ‐ Relevance for disorders of the central nervous system. Neurobiol Dis 97: 80‐89 [PMID:26829643] Merighi A. (2016) Targeting the glial‐derived neurotrophic factor and related molecules for controlling normal and pathologic pain. Expert Opin Ther Targets 20: 193‐208 [PMID:26863504]

Integrins

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).

Further reading on Integrins

Clemetson, KJ. (2017) The origins of major platelet receptor nomenclature. Platelets 28: 40‐42 [PMID:27715379] Hamidi, H et al. (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer 115: 1017‐1023 [PMID:27685444] Horton, ER et al. (2016) The integrin adhesome network at a glance. J Cell Sci 129: 4159‐4163 [PMID:27799358] Ley, K et al. (2016) Integrin‐based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15: 173‐83 [PMID:26822833] Manninen, A et al. (2017) A proteomics view on integrin‐mediated adhesions. Proteomics 17: [PMID:27723259] Park, YK et al. (2016) Integrins in synapse regulation. Nat Rev Neurosci 17: 745‐756 [PMID:27811927]

Natriuretic peptide receptor family

Natriuretic peptide receptors (NPRs, 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]. The polysaccharide obtained from fermentation of Aureobasidium species, HS142‐1, acts as an antagonist at both GC‐A and GC‐B receptors [133]. 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) [76]. GC‐D and GC‐G are pseudogenes in man.

Further reading on Natriuretic peptide receptor family

Blomain, ES et al. (2016) Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer. Mol Pharmacol 90: 199‐204 [PMID:27251363] Kuhn, M. (2016) Molecular Physiology of Membrane Guanylyl Cyclase Receptors. Physiol Rev 96: 751‐804 [PMID:27030537] Santhekadur, PK et al. (2017) The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed Pharmacother 92: 826‐835 [PMID:28599248] Theilig, F et al. (2015) ANP‐induced signaling cascade and its implications in renal pathophysiology. Am J Physiol Renal Physiol 308: F1047‐55 [PMID:25651559] Volpe, M et al. (2016) The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci (Lond) 130: 57‐77 [PMID:26637405]

Pattern recognition receptors

Pattern Recognition Receptors (PRRs, [173]) (nomenclature as agreed by NC‐IUPHAR sub‐committee on Pattern Recognition Receptors, [16]) 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 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. PRRs include both cell‐surface and intracellular proteins. PRRs may be divided into signalling‐associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation IL‐1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are: Catalytic PRRs (see links below this overview) Toll‐like receptors (TLRs) Nucleotide‐binding oligomerization domain‐like receptors (NLRs, also known as NOD‐like receptors) RIG‐I‐like receptors (RLRs)

Non‐catalytic pattern recognition receptors

Absent in melanoma (AIM)‐like receptors (ALRs) C‐type lectin‐like receptors (CLRs), and Other pattern recognition receptors.

Toll‐like receptor family

Members of the toll‐like family of receptors (nomenclature recommended by the NC‐IUPHAR subcommittee on pattern recognition receptors, [16]) 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, [174, 175]). 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) [161].

Further reading on Toll‐like receptor family

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] Goulopoulou S et al. (2016) Toll‐like Receptors in the Vascular System: Sensing the Dangers Within. Pharmacol Rev 68: 142‐67 [PMID:26721702] Micera A et al. (2016) Toll‐Like Receptors and Tissue Remodeling: The Pro/Cons Recent Findings. J Cell Physiol 231: 531‐44 [PMID:26248215] Zhang Z et al. (2017) Towards a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system. FEBS Lett [PMID:28686285] Zinngrebe J et al. (2017) TLRs Go Linear ‐ On the Ubiquitin Edge. Trends Mol Med 23: 296‐309 [PMID:28325627]

NOD‐like receptor family

The nucleotide‐binding oligomerization domain, leucine‐rich repeat (NLR) family of receptors (nomenclature recommended by the NC‐IUPHAR subcommittee on pattern recognition receptors [16]) 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 [177]. 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‐1(IL1B, P01584) and IL‐18(IL18, Q14116) [16, 32]. NLRP3 has also been reported to respond to host‐derived products, known as danger‐associated molecular patterns, or DAMPs, including uric acid [141], ATP, L‐glucose, hyaluronan and amyloid (APP, P05067) [161]. 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 on NOD‐like receptor family

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] Kong X et al. (2017) The function of NOD‐like receptors in central nervous system diseases. J Neurosci Res 95: 1565‐1573 [PMID:28029680] Motta V et al. (2015) NOD‐like receptors: versatile cytosolic sentinels. Physiol Rev 95: 149‐78 [PMID:25540141]

Receptor tyrosine kinases (RTKs)

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 [11, 57, 184]. In the human genome, 58 RTKs have been identified, which fall into 20 families [100]. 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‐, 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.

Type I RTKs: ErbB (epidermal growth factor) receptor family

ErbB family receptors are Class I receptor tyrosine kinases [57]. 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 [58]. 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 and lung cancer. Mutations in the EGFR are responsible for acquired resistance to tyrosine kinase inhibitor chemotherapeutics. [ 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, [50]), gefitinib, erlotinib and tyrphostins AG879 and AG1478.

Further reading on Type I RTKs: ErbB (epidermal growth factor) receptor family

Kobayashi Y et al. (2016) Not all EGFR mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. [PMID:27323238]

Type II RTKs: Insulin receptor family

The circulating peptide hormones insulin(INS, P01308) and the related insulin‐like growth factors (IGF) activate Class II receptor tyrosine kinases [57], 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. 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 2 receptor; IGF2R; P11717), 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 [93], 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 [197].

Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family

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. 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 [1].

Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

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(VEGFD, O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers. The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [45], Ki8751 [92] and ZM323881, a novel inhibitor of vascular endothelial growth factor‐receptor‐2 tyrosine kinase activity [193] 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

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 [8]. 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 [192]. 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 [105, 209]. PD161570 is an FGFR tyrosine kinase inhibitor [8], while PD173074 has been described to inhibit FGFR1 and FGFR3 [168].

Type VI RTKs: PTK7/CCK4

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]. Thus far, no selective PTK7 inhibitors have been described.

Type VII RTKs: Neurotrophin receptor/Trk family

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. [ and [ 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 [35]. Small molecule agonists of trkB have been described, including LM22A4 [124], while ANA12 has been described as a non‐competitive antagonist of BDNF binding to trkB [20]. GNF5837 is a family‐selective tyrosine kinase inhibitor [2], while the tyrosine kinase activity of the trkA receptor can be inhibited by GW441756(pIC50= 8.7, [198]) and tyrphostin AG879[162].

Type VIII RTKs: ROR family

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 [59].

Type IX RTKs: MuSK

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 [87]. Thus far, no selective MuSK inhibitors have been described.

Type X RTKs: HGF (hepatocyte growth factor) receptor family

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. PF04217903 is a selective Met tyrosine kinase inhibitor [29]. SU11274 is an inhibitor of the HGF receptor [185], with the possibility of further targets [5].

Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family

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. AXL tyrosine kinase inhibitors have been described [131].

Type XII RTKs: TIE family of angiopoietin receptors

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.

Type XIII RTKs: Ephrin receptor family

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.

Type XIV RTKs: RET

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. A number of tyrosine kinase inhibitors targeting RET have been described [43].

Type XV RTKs: RYK

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]. Thus far, no selective RYK inhibitors have been described.

Type XVI RTKs: DDR (collagen receptor) family

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). The tyrosine kinase inhibitors of DDR, imatinib and nilotinib, were identified from proteomic analysis [34]. 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

crizotinib is a tyrosine kinase inhibitor, anti‐cancer drug targeting ALK and ROS1.

Type XVIII RTKs: LMR family

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 [48], giving rise to the name AATYK (Apoptosis‐associated tyrosine kinase); while over‐expression induces differentiation in neuroblastoma cells [155]. As yet no selective inhibitors of the LMR family have been described.

Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

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 [138].

Type XX RTKs: STYK1

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 [38]. As yet, no selective inhibitors of STYK1 have been described.

Further reading on Receptor tyrosine kinases (RTKs)

Alvarez‐Aznar A et al. (2017) VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function. Curr Top Dev Biol 123: 433‐482 [PMID:28236974] Bergeron JJ et al. (2016) Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction. Annu Rev Biochem 85: 573‐97 [PMID:27023845] Carvalho S et al. (2016) Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti‐cancer antibodies: IUPHAR Review 18. Br J Pharmacol 173: 1407‐24 [PMID:26833433] De Silva DM et al. (2017) Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem Soc Trans [PMID:28673936] Eklund, L et al. (2017) Angiopoietin‐Tie signalling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 131 87‐103 [PMID:27941161] Katayama, R. (2017) Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)‐rearranged lung cancer. Pharmacol Ther [PMID:28185914] Kazlauskas, A. (2017) PDGFs and their receptors. Gene 614 1‐7 [PMID:28267575] Ke, EE et al. (2016) EGFR as a Pharmacological Target in EGFR‐Mutant Non‐Small‐Cell Lung Cancer: Where Do We Stand Now?. Trends Pharmacol Sci 37: 887‐903 [PMID:27717507] Kuwano, M et al. (2016) Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol Ther 161: 97‐110 [PMID:27000770] Lee, DH. (2017) Treatments for EGFR‐mutant non‐small cell lung cancer (NSCLC): The road to a success, paved with failures. Pharmacol Ther 174: 1‐21 [PMID:28167215] Nelson, KN et al. (2017) Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. Trends Mol Med 23: 59‐79 [PMID:27988109] Simons M et al. (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17: 611‐25 [PMID:27461391] Stricker S et al. (2017) ROR‐Family Receptor Tyrosine Kinases. Curr Top Dev Biol 123: 105‐142 [PMID:28236965] Tan, AC et al. (2017) Exploiting receptor tyrosine kinase co‐activation for cancer therapy. Drug Discov Today 22: 72‐84 [PMID:27452454]

Receptor serine/threonine kinase (RSTK) family

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 [103]. 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.

Type I receptor serine/threonine kinases

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).

Type II receptor serine/threonine kinases

Type III receptor serine/threonine kinases

RSTK functional heteromers

For the receptors listed on this page, the exact combination of subunits forming the functional heteromeric receptors is unknown. Comments on Receptor serine/threonine kinase (RSTK) family: A number of endogenous inhibitory ligands have been identified for RSTKs, including BMP‐3(BMP3, P12645), inhibin (INHA, P05111), inhibin (INHBC, P55103) and inhibin (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 [187]. The authors confirmed the selectivity of TGF‐beta RI inhibitor III to inhibit TGFβ signalling through ALK4, ALK5, ALK7 [31]. Dorsomorphin inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [207]. 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 on Receptor serine/threonine kinase (RSTK) family

Budi EH et al. (2017) Transforming Growth Factor‐beta Receptors and Smads: Regulatory Complexity and Functional Versatility. Trends Cell Biol [PMID:28552280] Chen W et al. (2016) Immunoregulation by members of the TGFbeta superfamily. Nat Rev Immunol 16: 723‐740 [PMID:27885276] Heger J. (2016) Molecular switches under TGFbeta signalling during progression from cardiac hypertrophy to heart failure. Br J Pharmacol 173: 3‐14 [PMID:26431212] Luo JY et al. (2015) Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system. J Physiol 593: 2995‐3011 [PMID:25952563] Macias MJ et al. (2015) Structural determinants of Smad function in TGF‐beta signaling. Trends Biochem Sci 40: 296‐308 [PMID:25935112] Morrell NW et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 13: 106‐20 [PMID:26461965] Neuzillet C et al. (2015) Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther 147: 22‐31 [PMID:25444759] van der Kraan PM. (2017) The changing role of TGFbeta in healthy, ageing and osteoarthritic joints. Nat Rev Rheumatol 13: 155‐163 [PMID:28148919]

Receptor tyrosine phosphatase (RTP) family

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.

Further reading on Receptor tyrosine phosphatase (RTP) family

He R et al. (2013) Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J. 280: 731‐50 [PMID:22816879] Papadimitriou E et al. (2016) Pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta as regulators of angiogenesis and cancer. Biochim Biophys Acta 1866: 252‐265 [PMID:27693125] Stanford SM et al. (2017) Targeting Tyrosine Phosphatases: Time to End the Stigma. Trends Pharmacol Sci 38: 524‐540 [PMID:28412041]

Tumour necrosis factor (TNF) receptor family

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. 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 on Tumour necrosis factor (TNF) receptor family

Blaser H et al. (2016) TNF and ROS Crosstalk in Inflammation. Trends Cell Biol 26: 249‐61 [PMID:26791157] Croft M et al. (2017) Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol 13: 217‐233 [PMID:28275260] Kalliolias GD et al. (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12: 49‐62 [PMID:26656660] Olesen CM et al. (2016) Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol Ther 159: 110‐9 [PMID:26808166] von Karstedt S et al. (2017) Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer 17: 352‐366 [PMID:28536452]
Nomenclature Interleukin‐2 receptor Interleukin‐4 receptor type I Interleukin‐4 receptor type II Interleukin‐7 receptor Interleukin‐9 receptor
Subunits Interleukin‐2 receptor subunit β (Ligand‐binding subunit), Interleukin‐2 receptor subunit γ (Other subunit), Interleukin‐2 receptor subunit α (Ligand‐binding subunit) Interleukin‐4 receptor subunit α (Ligand‐binding subunit), Interleukin‐2 receptor subunit γ (Other subunit) Interleukin‐13 receptor subunit α1 (Other subunit), Interleukin‐4 receptor subunit α (Ligand‐binding subunit) Interleukin‐2 receptor subunit γ (Other subunit), Interleukin‐7 receptor subunit α (Ligand‐binding subunit) Interleukin‐2 receptor subunit γ (Other subunit), Interleukin 9 receptor (Ligand‐binding subunit)
Endogenous agonists IL‐2 (IL2, P60568) IL‐4 (IL4, P05112) IL‐13 (IL13, P35225), IL‐4 (IL4, P05112) IL‐7 (IL7, P13232) IL‐9 (IL9, P15248)
Endogenous antagonists IL‐1 receptor antagonist (IL1RN, P18510)‐‐‐‐
Selective antagonists AF12198 [1]‐‐‐‐
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)
CommentsDecoy receptor that binds IL‐13 (IL13, P35225) as a monomer.–––
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 (pK d>8) [176], basiliximab –– dupilumab (pIC50 11.1) [140]–
Nomenclature Interleukin 9 receptor Interleukin‐13 receptor subunit α1 Interleukin‐15 receptor subunit α Interleukin 21 receptor Cytokine receptor‐like factor 2
HGNC, UniProt IL9R, Q01113 IL13RA1, P78552 IL15RA, Q13261 IL21R, Q9HBE5 CRLF2, Q9HC73
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 [134]–
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 (pK d 8.7) [109] mavrilimumab (pIC50 9.9) [32]–
Nomenclature Interleukin‐6 receptor Interleukin‐11 receptor Interleukin‐27 receptor Interleukin‐31 receptor Ciliary neutrophic factor receptor Leukemia inhibitory factor receptor Oncostatin‐M 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‐6 receptor, β subunit (Other subunit), Interleukin 27 receptor, alpha (Ligand‐binding 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) 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)
Endogenous agonists IL‐6 (IL6, P05231) [157] IL‐11 (IL11, P20809) IL‐27 (EBI3 IL27, Q14213 Q8NEV9) IL‐31 (IL31, Q6EBC2) CRCF1/CLCF1 heterodimer (CLCF1 CRLF1, O75462 Q9UBD9), ciliary neurotrophic factor (CNTF, P26441) LIF (LIF, P15018), cardiotrophin‐1 (CTF1, Q16619), oncostatin M (OSM, P13725) oncostatin M (OSM, P13725)
Agonists– oprelvekin [10, 195]–––––
Antibodies vobarilizumab (pK d 12.7) [185], sapelizumab (pK d 8.9) [92], tocilizumab (pK d 8.6)––––––
Nomenclature Interleukin‐6 receptor, α subunit Interleukin‐6 receptor, β subunit
Systematic nomenclatureinterleukin 6 receptorinterleukin 6 signal transducer
HGNC, UniProt IL6R, P08887 IL6ST, P40189
Common abreviationIL6RIL6ST
Endogenous agonists IL‐6 (IL6, P05231) [ 157]–
Antibodies sarilumab (Binding) (pK d 10.6–11.1) [198]–
Nomenclature Interleukin‐11 receptor, α subunit Interleukin 27 receptor, alpha Interleukin‐31 receptor, α subunit Ciliary neurotrophic factor receptor α subunit Leptin receptor Leukemia inhibitory factor receptor Oncostatin M‐specific receptor, β subunit
HGNC, UniProt IL11RA, Q14626 IL27RA, Q6UWB1 IL31RA, Q8NI17 CNTFR, P26992 LEPR, P48357 LIFR, P42702 OSMR, Q99650
Endogenous agonists–––– leptin (LEP, P41159) [187] – Mouse––
Nomenclature Interleukin‐12 receptor Interleukin‐23 receptor Interleukin‐12 receptor, β1 subunit Interleukin‐12 receptor, β2 subunit 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)–––
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) [44] G‐CSF (CSF3, P09919) growth hormone 1 (GH1, P01241), growth hormone 2 (GH2, P01242) prolactin (PRL, P01236) [46] – Mouse, choriomammotropin (CSH1 CSH2, P01243), chorionic somatomammotropin hormone‐like 1 (CSHL1, Q14406) thrombopoietin (THPO, P40225)
Agonists peginesatide [44] pegfilgrastim –– romiplostim
Selective agonists–––– eltrombopag [119]
Antagonists–– pegvisomant [179]––
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, P001569), 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]–
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 (pK d>10) [24]–––
Nomenclature Interleukin‐10 receptor Interleukin‐20 receptor Interleukin‐22α1/20β heteromer Interleukin‐22α1/10β heteromer Interleukin‐22 receptor α2 Interferon‐λ receptor 1
HGNC, UniProt–––– IL22RA2, Q969J5 –
Subunits Interleukin 10 receptor, α subunit (Ligand‐binding subunit), Interleukin 10 receptor, β subunit (Other subunit) Interleukin 20 receptor, β subunit (Other subunit), Interleukin 20 receptor, α subunit (Ligand‐binding subunit) Interleukin 22 receptor, α1 subunit (Ligand‐binding subunit), Interleukin 20 receptor, β subunit (Ligand‐binding subunit) Interleukin 22 receptor, α1 subunit (Ligand‐binding subunit), Interleukin 10 receptor, β subunit (Ligand‐binding subunit)– Interferon‐λ receptor subunit 1 (Ligand‐binding subunit), Interleukin 10 receptor, β subunit (Other subunit)
Endogenous agonists IL‐10 (IL10, P22301) IL‐19 (IL19, Q9UHD0), IL‐20 (IL20, Q9NYY1), IL‐24 (IL24, Q13007) IL‐20 (IL20, Q9NYY1), IL‐24 (IL24, Q13007) IL‐22 (IL22, Q9GZX6)– IFN‐λ1 (IFNL1, Q8IU54), IFN‐λ2 (IFNL2, Q8IZJ0), IFN‐λ3 (IFNL3, Q8IZI9)
Comments––––Soluble decoy receptor that binds IL‐22 (IL22, Q9GZX6) as a monomer.–
Nomenclature Interleukin 10 receptor, α subunit Interleukin 10 receptor, β subunit Interleukin 20 receptor, α subunit Interleukin 20 receptor, β subunit Interleukin 22 receptor, α1 subunit Interferon‐λ receptor subunit 1
HGNC, UniProt IL10RA, Q13651 IL10RB, Q08334 IL20RA, Q9UHF4 IL20RB, Q6UXL0 IL22RA1, Q8N6P7 IFNLR1, Q8IU57
Nomenclature Interleukin‐1 receptor, type I Interleukin‐33 receptor Interleukin‐36 receptor Interleukin‐1 receptor, type II Interleukin‐18 receptor
Subunits IL‐1 receptor accessory protein (Other subunit), Interleukin 1 receptor, type I (Ligand‐binding subunit) IL‐1 receptor accessory protein (Other subunit), Interleukin‐1 receptor‐like 1 (Ligand‐binding subunit) IL‐1 receptor accessory protein (Other subunit), Interleukin‐1 receptor‐like 2 (Ligand‐binding subunit) IL‐1 receptor accessory protein (Other subunit), Interleukin 1 receptor, type II (Ligand‐binding subunit) IL‐18 receptor accessory protein (Other subunit), Interleukin‐18 1 (Ligand‐binding subunit)
Inhibitors anakinra (pK d 7.8) [39]––––
Endogenous agonists IL‐1α (IL1A, P01583), IL‐1β (IL1B, P01584) IL‐33 (IL33, O95760) IL‐36α (IL36A, Q9UHA7), IL‐36β (IL36B, Q9NZH7), IL‐36γ (IL36G, Q9NZH8)– IL‐18 (IL18, Q14116), IL‐37 (IL37, Q9NZH6)
Endogenous antagonists IL‐1 receptor antagonist (IL1RN, P18510)– IL‐36 receptor antagonist (IL36RN, Q9UBH0)––
Selective antagonists AF12198 [1]––––
Comments–– IL‐36 receptor antagonist (IL36RN, Q9UBH0) is a highly selective antagonist of the response to IL‐36γ (IL36G, Q9NZH8).Decoy receptor that binds IL‐1α (IL1A, P01583), IL‐1β (IL1B, P01584) and IL‐1 receptor antagonist (IL1RN, P18510).–
Nomenclature Interleukin 1 receptor, type I Interleukin 1 receptor, type II Interleukin‐1 receptor‐like 1 Interleukin‐1 receptor‐like 2 Interleukin‐18 1
HGNC, UniProt IL1R1, P14778 IL1R2, P27930 IL1RL1, Q01638 IL1RL2, Q9HB29 IL18R1, Q13478
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)
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) [206]––––
Comments–––The endogenous agonist for this receptor is unknown.–
Nomenclature GDNF family receptor α1 GDNF family receptor α2 GDNF family receptor α3 GDNF family receptor α4
HGNC, UniProt GFRA1, P56159 GFRA2, O00451 GFRA3, O60609 GFRA4, Q9GZZ7
Common abreviationGFRα1GFRα2GFRα3GFRα4
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) [90, 180]–––
Nomenclature integrin α1β1 integrin α2β1 integrin αIIbβ3 integrin α4β1
Subunits integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 1 subunit integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 2 subunit (CD49B, alpha 2 subunit of VLA‐2 receptor) integrin, beta 3 subunit (platelet glycoprotein IIIa, antigen CD61), integrin, alpha IIb subunit (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA‐4 receptor)
Ligandscollagen, laminincollagen, laminin, thrombospondin fibrinogen (FGA FGB FGG, P02671 P02675 P02679), fibronectin (FN1, P02751), von Willebrand factor (VWF, P04275), vitronectin (VTN, P04004), thrombospondin fibronectin (FN1, P02751), vascular cell adhesion protein 1 (VCAM1, P19320), osteopontin (SPP1, P10451), thrombospondin
Inhibitors obtustatin (pIC50 9.1) [118] TCI15 (pIC50 7.9) [129] tirofiban (pIC50 9.4) [182], G4120 (pK i 8.4) [125, 204], GR 144053 (pIC50 7.4) [40], eptifibatide (pIC50 6.2–6.8) [160] BIO1211 (pIC50 8.3–9) [106], TCS2314
Antibodies–– abciximab [34] natalizumab [140]
Comments––– LDV‐FITC is used as a probe at this receptor.
Nomenclature integrin α4β7 integrin α5β1 integrin α6β1 integrin α10β1
Subunits integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA‐4 receptor), integrin, beta 7 subunit integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 5 subunit (fibronectin receptor, alpha polypeptide) integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 6 subunit integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 10 subunit
Ligands– fibronectin (FN1, P02751)laminincollagen
Antibodies vedolizumab (Antagonist) (pIC50 8.3) [172]–––
Nomenclature integrin α11β1 integrin αEβ7 integrin αLβ2 integrin αVβ3
Subunits integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12), integrin, alpha 11 subunit integrin, alpha E subunit (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide), integrin, beta 7 subunit integrin, beta 2 subunit (complement component 3 receptor 3 and 4 subunit), integrin, alpha L subunit (antigen CD11A (p180), lymphocyte function‐ associated antigen 1; alpha polypeptide) integrin, beta 3 subunit (platelet glycoprotein IIIa, antigen CD61), integrin, alpha V subunit
LigandscollagenE‐cadherin ICAM‐1 (ICAM1, P05362), ICAM‐2 (ICAM2, P13598) vitronectin (VTN, P04004), fibronectin (FN1, P02751), fibrinogen (FGA FGB FGG, P02671 P02675 P02679), osteopontin (SPP1, P10451), von Willebrand factor (VWF, P04275), thrombospondin, tenascin
Activators––– TP508 (pK d 7.9) [36]
Inhibitors–– A286982 (pIC50 7.4–7.5) [109] echistatin (pIC50 11.7) [99], P11 (pIC50 11.6) [99], cilengitide (pIC50 8.5) [56]
Antibodies––– etaracizumab (Binding) (pK d 6.3) [199]
Nomenclature integrin, alpha 1 subunit integrin, alpha 2 subunit (CD49B, alpha 2 subunit of VLA‐2 receptor) integrin, alpha IIb subunit (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41) integrin, alpha 3 subunit (antigen CD49C, alpha 3 subunit of VLA‐3 receptor) integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA‐4 receptor) integrin, alpha 5 subunit (fibronectin receptor, alpha polypeptide)
HGNC, UniProt ITGA1, P56199 ITGA2, P08514 ITGA2B, P17301 ITGA3, P26006 ITGA4, P13612 ITGA5, P08648
Ligands––– peptide ligand 2 (pIC50 7.2) [203]––
Antibodies–––– natalizumab [140]–
Nomenclature integrin, alpha 6 subunit integrin, alpha 7 subunit integrin, alpha 8 subunit integrin, alpha 9 subunit integrin, alpha 10 subunit integrin, alpha 11 subunit integrin, alpha D subunit
HGNC, UniProt ITGA6, P23229 ITGA7, Q13683 ITGA8, P53708 ITGA9, Q13797 ITGA10, O75578 ITGA11, Q9UKX5 ITGAD, Q13349
Nomenclature integrin, alpha E subunit (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide) integrin, alpha L subunit (antigen CD11A (p180), lymphocyte function‐associated antigen 1; alpha polypeptide) integrin, alpha M subunit (complement component 3 receptor 3 subunit) integrin, alpha V subunit integrin, alpha X subunit (complement component 3 receptor 4 subunit)
HGNC, UniProt ITGAE, P38570 ITGAL, P20701 ITGAM, P11215 ITGAV, P06756 ITGAX, P20702
Antagonists– lifitegrast (Inhibition) [20, 207]–––
Antibodies– efalizumab (Binding) (pK d 11.4) [96]–––
Nomenclature integrin, beta 2 subunit (complement component 3 receptor 3 and 4 subunit) integrin, beta 3 subunit (platelet glycoprotein IIIa, antigen CD61) integrin, beta 4 subunit integrin, beta 5 subunit integrin, beta 6 subunit integrin, beta 7 subunit integrin, beta 8 subunit
HGNC, UniProt ITGB1, P05556 ITGB2, P05107 ITGB3, P05106 ITGB4, P16144 ITGB5, P18084 ITGB6, P18564 ITGB7, P26010 ITGB8, P26012
Nomenclature Guanylyl cyclase‐A Guanylyl cyclase‐B Guanylyl cyclase‐C natriuretic peptide receptor 3
HGNC, UniProt NPR1, P16066 NPR2, P20594 GUCY2C, P25092 NPR3, P17342
Common abreviationGC‐AGC‐BGC‐CNPR‐C
Potency order atrial natriuretic peptide (NPPA, P01160) ≥brain natriuretic peptide (NPPB, P16860) ≫C‐type natriuretic peptide (NPPC, P23582) [172] C‐type natriuretic peptide (NPPC, P23582) ≫atrial natriuretic peptide (NPPA, P01160) ≫brain natriuretic peptide (NPPB, P16860) [172] uroguanylin (GUCA2B, Q16661) >guanylin (GUCA2A, Q02747) atrial natriuretic peptide (NPPA, P01160) >C‐type natriuretic peptide (NPPC, P23582) ≥brain natriuretic peptide (NPPB, P16860) [172]
Endogenous ligands atrial natriuretic peptide (NPPA, P01160) [210] brain natriuretic peptide (NPPB, P16860) [210] C‐type natriuretic peptide (NPPC, P23582) [172] guanylin (GUCA2A, Q02747), uroguanylin (GUCA2B, Q16661) osteocrin (OSTN, P61366) [148]
Selective agonists Dendroaspis natriuretic peptide [211], sANP [210], cenderitide [212] cenderitide [121], vosoritide [112] linaclotide [18, 65], E. coli heat‐stable enterotoxin (STa) [18], plecanatide [190] cANF4‐23 [132]
Selective antagonists A‐71915 pK i 9.2–9.5 [213], [Asu7,23']β‐ANP‐(7‐28) pK i 7.5 [14], anantin [215, 216], HS142‐1 [217] peptide P19 (pKd 7.8) [37], HS142‐1 [151], [Ser11](N‐CNP,C‐ANP)pBNP2‐15 [37], compound C10 [10]– AP811 (pK i 9.3) [186], M372049 [73]
Labelled ligands [125I]ANP (human) (Agonist) [125I]CNP (human) [125I]Sta (Agonist) [63] [125I]ANP (human)
Nomenclature TLR1 TLR2 TLR3 TLR4 TLR5
HGNC, UniProt TLR1, Q15399 TLR2, O60603 TLR3, O15455 TLR4, O00206 TLR5, O60602
Agonists– compound 13 [91], peptidoglycan [163, 205] poly(I:C) [5] LPS [150], paclitaxel [85] – Mouse flagellin [67]
Selective antagonists––– resatorvid [78]–
CommentsFunctions 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 [79]. TLR4 signals in conjunction with the co‐factor MD‐2 (LY96).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 [70], loxoribine [68], resiquimod [70, 83] resiquimod [70, 83]–––
Antagonists– hydroxychloroquine (pIC50 5.6) [96]– hydroxychloroquine (pIC50 7.1) [96]––
CommentsFunctions 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 [71]. Activated by CpG rich DNA sequences; pro‐inflammatory.TLR10 is the only pattern‐recognition receptor without known ligand specificity and biological function. Evidence suggests it plays a modulatory role with predominantly inhibitory (anti‐inflammatory) actions [145]. Murine TLR10 has a retroviral insertion that makes it non‐functional.Found in mouse
Nomenclature nucleotide binding oligomerization domain containing 1 nucleotide binding oligomerization domain containing 2 NLRC3 NLRC4 NLRC5 NLRX1 CIITA
HGNC, UniProt NOD1, Q9Y239 NOD2, Q9HC29 NLRC3, Q7RTR2 NLRC4, Q9NPP4 NLRC5, Q86WI3 NLRX1, Q86UT6 CIITA, P33076
Common abreviationNOD1NOD2–––––
Agonists meso‐DAP muramyl dipeptide –––––
Comments–NOD2 has also been reported to be activated by ssRNA [158] 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 NLRP1 NLRP2 NLRP3 NLRP4 NLRP5 NLRP6 NLRP7
HGNC, UniProt NLRP1, Q9C000 NLRP2, Q9NX02 NLRP3, Q96P20 NLRP4, Q96MN2 NLRP5, P59047 NLRP6, P59044 NLRP7, Q8WX94
Inhibitors–– MCC950 (pIC50>8) [25]––––
Agonists muramyl dipeptide ––––––
CommentsNLRP1 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.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.––Absent in mouse. Along with NLRP2 the product of a primate‐specific gene duplication.
Nomenclature NLRP8 NLRP9 NLRP10 NLRP11 NLRP12 NLRP13 NLRP14
HGNC, UniProt NLRP8, Q86W28 NLRP9, Q7RTR0 NLRP10, Q86W26 NLRP11, P59045 NLRP12, P59046 NLRP13, Q86W25 NLRP14, Q86W24
CommentsAbsent in mouseThis receptor has three murine orthologues.–Absent in mouse–Absent in mouse–
Nomenclature epidermal growth factor receptor erb‐b2 receptor tyrosine kinase 2 erb‐b2 receptor tyrosine kinase 3 erb‐b2 receptor tyrosine kinase 4
HGNC, UniProt EGFR, P00533 ERBB2, P04626 ERBB3, P21860 ERBB4, Q15303
EC number 2.7.10.1 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationEGFRHER2HER3HER4
Endogenous ligands EGF (EGF, P01133), HB‐EGF (HBEGF, Q99075), TGFα (TGFA, P01135), amphiregulin (AREG, P15514), betacellulin (BTC, P35070), epigen (EPGN, Q6UW88), epiregulin (EREG, O14944)– neuregulin‐1 (NRG1, Q02297), neuregulin‐2 (NRG2, O14511) HB‐EGF (HBEGF, Q99075), betacellulin (BTC, P35070), epiregulin (EREG, O14944), neuregulin‐1 (NRG1, Q02297), neuregulin‐2 (NRG2, O14511), neuregulin‐3 (NRG3, P56975), neuregulin‐4 (NRG4, Q8WWG1)
Inhibitors canertinib (pK d 9.7) [33], afatinib (pK d 9.6) [33], tesevatinib (pIC50 9.5) [63], afatinib (pIC50 8–9.3) [36, 119], erlotinib (pK d 9.2) [33], gefitinib (pK d 9) [33], poziotinib (pIC50 8.3) [139], neratinib (pK d 8.2) [33], lapatinib (pK d 8.1) [33], CP‐724714 (pIC50 7.9) [60], tesevatinib (pIC50 7.8) [63], BMS‐690514 (pIC50 7.7) [117]– poziotinib (pIC50 7.6) [139]
Antibodies necitumumab (Binding) (pK d 9.5) [128], cetuximab (Binding) (pK d 9.4) [66] pertuzumab (Inhibition) (pIC50>8) [100], trastuzumab (Inhibition)––
Nomenclature Insulin receptor Insulin‐like growth factor I receptor Insulin receptor‐related receptor
HGNC, UniProt INSR, P06213 IGF1R, P08069 INSRR, P14616
EC number 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationInsRIGF1RIRR
Inhibitors– BMS‐754807 (pIC50 8.7) [198], GSK‐1838705A (pIC50 8.7) [159], GSK‐1838705A (pK d 8.1) [33], PQ401 (pIC50>6) [47], AG 1024 (pIC50 4.7) [153]–
Selective inhibitors– NVP‐AEW541 (pIC50 9.4) [49]–
Endogenous agonists insulin (INS, P01308) insulin‐like growth factor 1 (IGF1, P05019), insulin‐like growth factor 2 (IGF2, P01344)–
Nomenclature platelet derived growth factor receptor alpha platelet derived growth factor receptor beta KIT proto‐oncogene receptor tyrosine kinase
HGNC, UniProt PDGFRA, P16234 PDGFRB, P09619 KIT, P10721
EC number 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationPDGFRα PDGFRβ Kit
Endogenous ligandsPDGFPDGF–
Inhibitors PP121 (pIC50 8.7) [4], crenolanib (pK d 8.7) [69], ENMD‐2076 (pIC50 7.2) [149] crenolanib (pK d 8.5) [69], SU‐14813 (pIC50 8.4) [147], famitinib (pIC50 8.4) [21], sunitinib (pIC50 8.2) [89], sunitinib (pK i 8.1) [127] sunitinib (pK d 9.4) [33], famitinib (pIC50 8.7) [21], masitinib (pK d 8.1) [33], SU‐14813 (pIC50 7.8) [147], AKN‐028 (pIC50 7.5) [42], sorafenib (pIC50 7.2) [196]
Selective inhibitors CP‐673451 (pIC50 8) [156] CP‐673451 (pIC50 9) [156]–
Endogenous agonists–– stem cell factor (KITLG, P21583) [183]
Nomenclature colony stimulating factor 1 receptor fms related tyrosine kinase 3
HGNC, UniProt CSF1R, P07333 FLT3, P36888
EC number 2.7.10.1 2.7.10.1
Common abreviationCSFRFLT3
Endogenous ligands G‐CSF (CSF3, P09919), GM‐CSF (CSF2, P04141), M‐CSF (CSF1, P09603) Fms‐related tyrosine kinase 3 ligand (FLT3LG, P49771)
Inhibitors JNJ‐28312141 (pIC50 9.2) [116], Ki‐20227 (pK d 9.1) [33], Ki‐20227 (pIC50 8.7) [143], GW‐2580 (pK d 8.7) [33], JNJ‐28312141 (pK d 8.5) [33] AC710 (pK d 9.3) [108], linifanib (pK d 9.2) [33], dovitinib (pK d 9.2) [33], crenolanib (pK d 9.1) [69], AST‐487 (pK d 9.1) [33], ENMD‐2076 (pIC50 8.5) [149], tandutinib (pK d 8.5) [33]
Selective inhibitors GW‐2580 (pIC50 7.2) [27] G749 (pIC50 9.4) [97]
CommentsUpregulation of CSF1R expression is associated with migroglial activation and immune pathology in Alzhermer's disease (AD) [67, 61]. Pharmacological inhibition of CSF1R with GW‐2580 reduces microglial proliferation and prevents disease progression in a mouse model of AD, but this does not correlate with amyloid‐β plaque numbers [144]. 5'‐fluoroindirubinoxime has been described as a selective FLT3 inhibitor [22].
Nomenclature fms related tyrosine kinase 1 kinase insert domain receptor fms related tyrosine kinase 4
HGNC, UniProt FLT1, P17948 KDR, P35968 FLT4, P35916
EC number 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationVEGFR‐1VEGFR‐2VEGFR‐3
Endogenous ligands VEGFA (VEGFA, P15692), VEGFB (VEGFB, P49765) VEGFA (VEGFA, P15692), VEGFC (VEGFC, P49767), VEGFE (PDGFC, Q9NRA1) VEGFC (VEGFC, P49767), VEGFD (VEGFD, O43915), VEGFE (PDGFC, Q9NRA1)
Inhibitors SU‐14813 (pIC50 8.7) [147], CEP‐11981 (pIC50 8.5) [75], semaxanib (pIC50 8.1) [12] axitinib (pIC50 9.6) [98], cabozantinib (pIC50 9.5) [200], foretinib (pIC50 8.2–9.1) [137], cediranib (pK d 9) [33], tesevatinib (pIC50 8.8) [51], SU‐14813 (pK d 8.6) [33], motesanib (pK d 8.6) [33], famitinib (pIC50 8.3) [21], axitinib (pK d 8.2) [33] tesevatinib (pIC50 8.1) [51], sunitinib (pIC50 8.1) [86], nintedanib (pIC50 7.9) [72]
Sub/family‐selective inhibitors pazopanib (pIC50 8) [66] pazopanib (pK d 7.8) [33], pazopanib (pIC50 7.5) [79] pazopanib (pIC50 7.3) [66]
Antibodies– ramucirumab (Antagonist) (pIC50 9) [113]–
Nomenclature fibroblast growth factor receptor 1 fibroblast growth factor receptor 2 fibroblast growth factor receptor 3 fibroblast growth factor receptor 4
HGNC, UniProt FGFR1, P11362 FGFR2, P21802 FGFR3, P22607 FGFR4, P22455
EC number 2.7.10.1 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationFGFR1FGFR2FGFR3FGFR4
Endogenous ligands FGF‐1 (FGF1, P05230), FGF‐2 (FGF2, P09038), FGF‐4 (FGF4, P08620) >FGF‐5 (FGF5, P12034), FGF‐6 (FGF6, P10767) [146] FGF‐1 (FGF1, P05230) >FGF‐4 (FGF4, P08620), FGF‐7 (FGF7, P21781), FGF‐9 (FGF9, P31371) >FGF‐2 (FGF2, P09038), FGF‐6 (FGF6, P10767) [146] FGF‐1 (FGF1, P05230), FGF‐2 (FGF2, P09038), FGF‐9 (FGF9, P31371) >FGF‐4 (FGF4, P08620), FGF‐8 (FGF8, P55075) [146] FGF‐1 (FGF1, P05230), FGF‐2 (FGF2, P09038), FGF‐4 (FGF4, P08620), FGF‐9 (FGF9, P31371) >FGF‐6 (FGF6, P10767), FGF‐8 (FGF8, P55075) [146]
Sub/family‐selective inhibitors LY2874455 (pIC50 8.6) [205] LY2874455 (pIC50 8.6) [205] LY2874455 (pIC50 8.2) [205] LY2874455 (pIC50 8.2) [205]
Selective inhibitors––– BLU9931 (pIC50 8.5) [75]
Agonists– palifermin ––
Nomenclature protein tyrosine kinase 7 (inactive)
HGNC, UniProt PTK7, Q13308
EC number 2.7.10.1
Common abreviationCCK4
Nomenclature neurotrophic receptor tyrosine kinase 1 neurotrophic receptor tyrosine kinase 2 neurotrophic receptor tyrosine kinase 3
HGNC, UniProt NTRK1, P04629 NTRK2, Q16620 NTRK3, Q16288
EC number 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationtrkAtrkBtrkC
Endogenous ligands NGF (NGF, P01138) >neurotrophin‐3 (NTF3, P20783) BDNF (BDNF, P23560), neurotrophin‐4 (NTF4, P34130) >neurotrophin‐3 (NTF3, P20783) neurotrophin‐3 (NTF3, P20783)
Inhibitors compound 2c (pIC50 8.9) [189], milciclib (pIC50 7.3) [14]––
Sub/family‐selective inhibitors AZD1332 (pIC50>8.3) [9], GNF‐5837 (pIC50 8) [2] AZD1332 (pIC50>8.3) [9], GNF‐5837 (pIC50 8.1) [2] AZD1332 (pIC50>8.3) [9], GNF‐5837 (pIC50 8.1) [2]
Nomenclature receptor tyrosine kinase like orphan receptor 1 receptor tyrosine kinase like orphan receptor 2
HGNC, UniProt ROR1, Q01973 ROR2, Q01974
EC number 2.7.10.1 2.7.10.1
Common abreviationROR1ROR2
Nomenclature muscle associated receptor tyrosine kinase
HGNC, UniProt MUSK, O15146
EC number 2.7.10.1
Common abreviationMuSK
Nomenclature MET proto‐oncogene, receptor tyrosine kinase macrophage stimulating 1 receptor
HGNC, UniProt MET, P08581 MST1R, Q04912
EC number 2.7.10.1 2.7.10.1
Common abreviationMETRon
Endogenous ligands hepatocyte growth factor (HGF, P14210) macrophage stimulating protein 1 (MST1, P09603)
Inhibitors capmatinib (pIC50 9.9) [111], SGX‐523 (pK d 9.7) [33], PHA‐665752 (pK d 9.6) [33], foretinib (pIC50 9.3–9.4) [104, 137], cabozantinib (pIC50 8.9) [200] BMS‐777607 (pIC50 8.7) [162]
Selective inhibitors SGX‐523 (pIC50 8.4) [17]–
Nomenclature AXL receptor tyrosine kinase TYRO3 protein tyrosine kinase MER proto‐oncogene, tyrosine kinase
HGNC, UniProt AXL, P30530 TYRO3, Q06418 MERTK, Q12866
EC number 2.7.10.1 2.7.10.1 2.7.10.1
Common abreviationAxlTyro3Mer
Endogenous ligands growth arrest specific protein 6 (GAS6, Q14393) [138], protein S (PROS1, P07225) [171] growth arrest specific protein 6 (GAS6, Q14393) [138], protein S (PROS1, P07225) [171] growth arrest specific protein 6 (GAS6, Q14393) [138]
Nomenclature tyrosine kinase with immunoglobulin like and EGF like domains 1 TEK receptor tyrosine kinase
HGNC, UniProt TIE1, P35590 TEK, Q02763
EC number 2.7.10.1 2.7.10.1
Common abreviationTIE1TIE2
Endogenous ligands– angiopoietin‐1 (ANGPT1, Q15389), angiopoietin‐4 (ANGPT4, Q9Y264)
Nomenclature EPH receptor A1 EPH receptor A2 EPH receptor A3 EPH receptor A4 EPH receptor A5 EPH receptor A6 EPH receptor A7
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
Common abreviationEphA1EphA2EphA3EphA4EphA5EphA6EphA7
Nomenclature EPH receptor A8 EPH receptor A10 EPH receptor B1 EPH receptor B2 EPH receptor B3 EPH receptor B4 EPH receptor B6
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
Common abreviationEphA8EphA10EphB1EphB2EphB3EphB4EphB6
Inhibitors–– compound 66 (pIC50 9) [95]–– tesevatinib (pIC50 8.9) [51]–
Nomenclature ret proto‐oncogene
HGNC, UniProt RET, P07949
EC number 2.7.10.1
Common abreviationRet
Inhibitors tamatinib (pIC50 8.3) [23], vandetanib (pK d 7.5) [33]
Nomenclature receptor‐like tyrosine kinase
HGNC, UniProt RYK, P34925
EC number 2.7.10.1
Common abreviationRYK
Nomenclature discoidin domain receptor tyrosine kinase 1 discoidin domain receptor tyrosine kinase 2
HGNC, UniProt DDR1, Q08345 DDR2, Q16832
EC number 2.7.10.1 2.7.10.1
Common abreviationDDR1DDR2
Nomenclature c‐ros oncogene 1, receptor tyrosine kinase
HGNC, UniProt ROS1, P08922
EC number 2.7.10.1
Common abreviationROS
Nomenclature apoptosis associated tyrosine kinase lemur tyrosine kinase 2 lemur tyrosine kinase 3
HGNC, UniProt AATK, Q6ZMQ8 LMTK2, Q8IWU2 LMTK3, Q96Q04
EC number 2.7.11.1 2.7.11.1 2.7.11.1
Common abreviationLmr1Lmr2Lmr3
Nomenclature leukocyte receptor tyrosine kinase ALK receptor tyrosine kinase
HGNC, UniProt LTK, P29376 ALK, Q9UM73
EC number 2.7.10.1 2.7.10.1
Common abreviationLTKALK
Inhibitors– GSK‐1838705A (pIC50 9.3) [159], compound 8e (pIC50 9.1) [74], crizotinib (pIC50 9) [30], NVP‐TAE684 (pK d 9) [33], compound 25b (pIC50 8.7) [53]
Selective inhibitors– ceritinib (pIC50 9.7) [120]
Comments– crizotinib appears to be a selective ALK inhibitor acting on the tyrosine kinase activity [52]
Nomenclature serine/threonine/tyrosine kinase 1
HGNC, UniProt STYK1, Q6J9G0
EC number 2.7.10.2
Common abreviationSTYK1
Nomenclature activin A receptor type IL activin A receptor type 1 bone morphogenetic protein receptor type IA activin A receptor type 1B transforming growth factor beta receptor 1 bone morphogenetic protein receptor type IB activin A receptor type 1C
HGNC, UniProt ACVRL1, P37023 ACVR1, Q04771 BMPR1A, P36894 ACVR1B, P36896 TGFBR1, P36897 BMPR1B, O00238 ACVR1C, Q8NER5
Common abreviationALK1ALK2BMPR1AALK4TGFBR1BMPR1BALK7
Inhibitors ML347 (pIC50 7.5) [41]– LY2109761 (pK i 7.4) [126], compound 15b (pIC50 7.1) [102]–
Selective inhibitors––– EW‐7197 (pIC50 7.9) [82] EW‐7197 (pIC50 8) [82]––
Nomenclature activin A receptor type 2A activin A receptor type 2B anti‐Mullerian hormone receptor type 2 bone morphogenetic protein receptor type 2 transforming growth factor beta receptor 2
HGNC, UniProt ACVR2A, P27037 ACVR2B, Q13705 AMHR2, Q16671 BMPR2, Q13873 TGFBR2, P37173
Common abreviationActR2ActR2BMISR2BMPR2TGFBR2
Antibodies– bimagrumab (pK d 11.8) [13]–––
Nomenclature transforming growth factor beta receptor 3
HGNC, UniProt TGFBR3, Q03167
Common abreviationTGFBR3
Nomenclature Transforming growth factor β receptor Bone morphogenetic protein receptors
Subunits transforming growth factor beta receptor 1 (Type I), transforming growth factor beta receptor 3 (Type III), transforming growth factor beta receptor 2 (Type II) bone morphogenetic protein receptor type IB (Type I), activin A receptor type 2B (Type II), activin A receptor type 2A (Type II), activin A receptor type IL (Type I), activin A receptor type 1 (Type I), bone morphogenetic protein receptor type IA (Type I), bone morphogenetic protein receptor type 2 (Type II)
CouplingSmad2, Smad3 [135, 167]Smad1, Smad5, Smad8 [153, 167]
Endogenous agonists TGFβ1 (TGFB1, P01137), TGFβ2 (TGFB2, P61812), TGFβ3 (TGFB3, P10600) BMP‐10 (BMP10, O95393), BMP‐2 (BMP2, P12643), BMP‐4 (BMP4, P12644), BMP‐5 (BMP5, P22003), BMP‐6 (BMP6, P22004), BMP‐7 (BMP7, P18075), BMP‐8A (BMP8A, Q7Z5Y6), BMP‐8B (BMP8B, P34820), BMP‐9 (GDF2, Q9UK05)
Nomenclature Growth/differentiation factor receptors Activin receptors Anti‐Müllerian hormone receptors
Subunits transforming growth factor beta receptor 1 (Type I), bone morphogenetic protein receptor type IB (Type I), activin A receptor type 2B (Type II), activin A receptor type 2A (Type II), activin A receptor type 1C (Type I), bone morphogenetic protein receptor type IA (Type I), activin A receptor type 1B (Type I), bone morphogenetic protein receptor type 2 (Type II) activin A receptor type 2B (Type II), activin A receptor type 2A (Type II), activin A receptor type 1C (Type I), activin A receptor type 1B (Type I) anti‐Mullerian hormone receptor type 2 (Type II), bone morphogenetic protein receptor type IB (Type I), activin A receptor type 1 (Type I), bone morphogenetic protein receptor type IA (Type I)
CouplingSmad1, Smad5, Smad8 [135, 167]Smad2, Smad3 [167]Smad1, Smad5, Smad8 [135, 167]
Endogenous agonists growth/differentiation factor‐1 (GDF1, P27539), growth/differentiation factor‐10 (GDF10, P55107), growth/differentiation factor‐3 (GDF3, Q9NR23), growth/differentiation factor‐7 (GDF7, Q7Z4P5), growth/differentiation factor‐9 (GDF9, O60383) activin A (INHBA, P08476), activin AB (INHBA INHBB, P08476 P09529), activin B (INHBB, P09529), inhibin A (INHA INHBA, P05111 P08476) Müllerian inhibiting substance (AMH, P03971)
Comments–Activin receptors are heteromeric complexes comprising activin receptor type I and type II subunits.–
Nomenclature HGNC gene symbol Uniprot ID Other names
Smad1 SMAD1 Q15797 JV4‐1, MADH1, MADR1
Smad2 SMAD2 Q15796 JV18‐1, MADH2, MADR2
Smad3 SMAD3 P84022 HsT17436, JV15‐2, MADH3
Smad4 SMAD4 Q13485 DPC4, MADH4
Smad5 SMAD5 Q99717 Dwfc, JV5‐1, MADH5
Smad6 SMAD6 O43541 HsT17432, MADH6, MADH7
Smad7 SMAD7 O15105 MADH7, MADH8
Smad8 SMAD9 O15198 MADH6, MADH9
Nomenclature RTP Type A RTP Type B RTP Type C RTP Type D RTP Type E RTP Type F RTP Type G
HGNC, UniProt PTPRA, P18433 PTPRB, P23467 PTPRC, P08575 PTPRD, P23468 PTPRE, P23469 PTPRF, P10586 PTPRG, P23470
Putative endogenous ligands–– galectin‐1 (LGALS1, P09382) [188] netrin‐G3 ligand (LRRC4B, Q9NT99) [94]– netrin‐G3 ligand (LRRC4B, Q9NT99) [94] contactin‐3 (CNTN3, Q9P232), contactin‐4 (CNTN4, Q8IWV2), contactin‐5 (CNTN5, O94779), contactin‐6 (CNTN6, Q9UQ52) [13]
Inhibitors––––– illudalic acid (pIC50 5.9) [107] compound 1 (pK i 5.6) [166]
Nomenclature RTP Type H RTP Type J RTP Type K RTP Type M RTP Type N RTP Type N2 RTP Type O
HGNC, UniProt PTPRH, Q9HD43 PTPRJ, Q12913 PTPRK, Q15262 PTPRM, P28827 PTPRN, Q16849 PTPRN2, Q92932 PTPRO, Q16827
Putative endogenous ligands–– galectin‐3 (LGALS3, P17931), galectin‐3 binding protein (LGALS3BP, Q08380) [88]––––
Nomenclature RTP Type Q RTP Type R RTP Type S RTP Type T RTP Type U RTP Type Z1
HGNC, UniProt PTPRQ, Q9UMZ3 PTPRR, Q15256 PTPRS, Q13332 PTPRT, O14522 PTPRU, Q92729 PTPRZ1, P23471
Putative endogenous ligands–– chondroitin sulphate proteoglycan 3 (NCAN, O14594), netrin‐G3 ligand (LRRC4B, Q9NT99) [94, 165]–– contactin‐1 (CNTN1, Q12860), pleiotrophin (PTN, C9JR52) (acts as a negative regulator) [13, 128]
Nomenclature tumor necrosis factor receptor 1 tumor necrosis factor receptor 2 lymphotoxin β receptor OX40 CD40 Fas decoy receptor 3
Systematic nomenclatureTNFRSF1ATNFRSF1BTNFRSF3TNFRSF4TNFRSF5TNFRSF6TNFRSF6B
HGNC, UniProt TNFRSF1A, P19438 TNFRSF1B, P20333 LTBR, P36941 TNFRSF4, P43489 CD40, P25942 FAS, P25445 TNFRSF6B, O95407
Adaptor proteinsTRADDTRAF1, TRAF2, TRAF5TRAF3, TRAF4, TRAF5TRAF1, TRAF2, TRAF3, TRAF5TRAF1, TRAF2, TRAF3, TRAF5, TRAF6FADD–
Common abreviationTNFR1TNFR2–––––
Endogenous ligands lymphotoxin‐α (LTA, P01374), tumour necrosis factor membrane form (TNF, P01375), tumour necrosis factor shed form (TNF, P01375) lymphotoxin‐α (LTA, P01374), tumour necrosis factor membrane form (TNF, P01375) LIGHT (TNFSF14, O43557), lymphotoxin β2α1 heterotrimer (LTA LTB, P01374 Q06643) OX‐40 ligand (TNFSF4, P23510) CD40 ligand (CD40LG, P29965) Fas ligand (FASLG, P48023)–
Inhibitors––– compound 1 (pIC50 5.9) [169]–––
Comments–––The OX40/OX40L pair is involved in late T‐cell costimulatory signaling and both are transiently expressed following antigen recognition, and blocking OX40/OX40L is reported to prevent the development of disease in in vivo autoimmune and inflammatory disease models [191]––Decoy receptor for LIGHT (TNFSF14, O43557), TL1A (TNFSF15, O95150) and Fas ligand (FASLG, P48023).
Nomenclature CD27 CD30 4‐1BB death receptor 4 death receptor 5 decoy receptor 1 decoy receptor 2
Systematic nomenclatureTNFRSF7TNFRSF8TNFRSF9TNFRSF10ATNFRSF10BTNFRSF10CTNFRSF10D
HGNC, UniProt CD27, P26842 TNFRSF8, P28908 TNFRSF9, Q07011 TNFRSF10A, O00220 TNFRSF10B, O14763 TNFRSF10C, O14798 TNFRSF10D, Q9UBN6
Adaptor proteinsTRAF2, SIVATRAF1, TRAF2, TRAF3, TRAF5TRAF1, TRAF2, TRAF3FADDFADD––
Common abreviation–––DR4DR5––
Endogenous ligands CD70 (CD70, P32970) CD30 ligand (TNFSF8, P32971) 4‐1BB ligand (TNFSF9, P41273) TRAIL (TNFSF10, P50591)–––
Endogenous agonists–––– TRAIL (TNFSF10, P50591) [208]––
Agonists––– SC‐67655 [77]–––
Antibodies– brentuximab vedotin (Inhibition)–– tigatuzumab (Agonist) (pK d∼8.5) [208]––
Comments–––––Decoy receptor for TRAIL (TNFSF10, P50591).Decoy receptor for TRAIL (TNFSF10, P50591).
Nomenclature receptor activator of NF‐kappa B osteoprotegerin death receptor 3 TWEAK receptor TACI BAFF receptor herpes virus entry mediator
Systematic nomenclatureTNFRSF11ATNFRSF11BTNFRSF25TNFRSF12ATNFRSF13BTNFRSF13CTNFRSF14
HGNC, UniProt TNFRSF11A, Q9Y6Q6 TNFRSF11B, O00300 TNFRSF25, Q93038 TNFRSF12A, Q9NP84 TNFRSF13B, O14836 TNFRSF13C, Q96RJ3 TNFRSF14, Q92956
Adaptor proteinsTRAF1, TRAF2, TRAF3, TRAF5, TRAF6–TRADDTRAF1, TRAF2, TRAF3TRAF2, TRAF5, TRAF6TRAF3TRAF2, TRAF3, TRAF5
Common abreviationRANKOPGDR3––BAFF‐RHVEM
Endogenous ligands RANK ligand (TNFSF11, O14788)– TL1A (TNFSF15, O95150) TWEAK (TNFSF12, O43508) APRIL (TNFSF13, O75888), BAFF (TNFSF13B, Q9Y275) BAFF (TNFSF13B, Q9Y275) B and T lymphocyte attenuator (BTLA, Q7Z6A9), LIGHT (TNFSF14, O43557), lymphotoxin‐α (LTA, P01374)
Comments–Acts as a decoy receptor for RANK ligand (TNFSF11, O14788) and possibly for TRAIL (TNFSF10, P50591).The only known TNFSF ligand for DR3 is TNF‐like protein 1A (TL1A) [218].––––
Nomenclature nerve growth factor receptor B cell maturation antigen glucocorticoid‐induced TNF receptor toxicity and JNK inducer RELT death receptor 6
Systematic nomenclatureTNFRSF16TNFRSF17TNFRSF18TNFRSF19TNFRSF19LTNFRSF21
HGNC, UniProt NGFR, P08138 TNFRSF17, Q02223 TNFRSF18, Q9Y5U5 TNFRSF19, Q9NS68 RELT, Q969Z4 TNFRSF21, O75509
Adaptor proteinsTRAF2, TRAF4, TRAF6TRAF1, TRAF2, TRAF3, TRAF5, TRAF6TRAF1, TRAF2, TRAF3, SIVATRAF1, TRAF2, TRAF3, TRAF5TRAF1TRADD
Common abreviation–BCMAGITRTAJ–DR6
Endogenous ligands NGF (NGF, P01138) (pIC50 6) [97], BDNF (BDNF, P23560), neurotrophin‐3 (NTF3, P20783), neurotrophin‐4 (NTF4, P34130) APRIL (TNFSF13, O75888), BAFF (TNFSF13B, Q9Y275) TL6 (TNFSF18, Q9UNG2) lymphotoxin‐α (LTA, P01374)––
CommentsOne of the two receptor types for the neurotrophins (factors that stimulate neuronal cell survival and differentiation). The other family of neurotrophin receptors are the Trk family of receptor tyrosine kinases.––Believed to be essential during embryonic development.Abundant in hematologic tissues. Selective receptor for TNF receptor‐associated factor 1 (TRAF1). Activates the NF‐κB pathway.–
Nomenclature TNFRSF22 TNFRSF23 ectodysplasin A2 isoform receptor ectodysplasin 1, anhidrotic receptor
Systematic nomenclature––TNFRS27–
HGNC, UniProt–– EDA2R, Q9HAV5 EDAR, Q9UNE0
Adaptor proteins––TRAF1, TRAF3, TRAF6TRAF1, TRAF2, TRAF3
Endogenous ligands–– ectodysplasin A2 (EDA, Q92838) [201] ectodysplasin A1 (EDA, Q92838) [201]
CommentsOnly identified in mouse to date. A potential decoy receptor for the cytotoxic ligand TNFSF10/TRAIL. Does not contain a cytoplasmic death domain so does not induce apoptosis, and does not activate the NF‐κB signalling pathway.Only identified in mouse to date. A potential decoy receptor for the cytotoxic ligand TNFSF10/TRAIL. Does not contain a cytoplasmic death domain so does not induce apoptosis, and does not activate the NF‐κB signalling pathway.Receptor for the EDA‐A2 isoform of ectodysplasin encoded by the anhidrotic ectodermal dysplasia (EDA) gene.Cell surface receptor for ectodysplasin A (a morphogen involved in the development of ectodermal tissues, including skin, hair, nails, teeth, and sweat glands).
  2 in total

Review 1.  Lateral signaling enhances TGF-beta response complexity.

Authors:  Stacey DaCosta Byfield; Anita B Roberts
Journal:  Trends Cell Biol       Date:  2004-03       Impact factor: 20.808

2.  THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Catalytic receptors.

Authors:  Stephen Ph Alexander; Doriano Fabbro; Eamonn Kelly; Neil V Marrion; John A Peters; Elena Faccenda; Simon D Harding; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies
Journal:  Br J Pharmacol       Date:  2017-12       Impact factor: 8.739
  2 in total
  163 in total

Review 1.  Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.

Authors:  Kelly L Wentworth; Umesh Masharani; Edward C Hsiao
Journal:  Br J Clin Pharmacol       Date:  2019-01-06       Impact factor: 4.335

2.  Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis.

Authors:  Carla Bastida; Virginia Ruiz-Esquide; Mariona Pascal; Aurelia H M de Vries Schultink; Jordi Yagüe; Raimon Sanmartí; Alwin D R Huitema; Dolors Soy
Journal:  Br J Clin Pharmacol       Date:  2018-02-07       Impact factor: 4.335

3.  Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury.

Authors:  Yaqi Zhou; Xianqiu Zeng; Ge Li; Qiuhua Yang; Jiean Xu; Min Zhang; Xiaoxiao Mao; Yapeng Cao; Lina Wang; Yiming Xu; Yong Wang; Yu Zhang; Zhengshuang Xu; Chaodong Wu; Jiang-Fan Chen; Md Nasrul Hoda; Zhiping Liu; Mei Hong; Yuqing Huo
Journal:  Br J Pharmacol       Date:  2019-05-21       Impact factor: 8.739

4.  An alternative intermittent eltrombopag dosing protocol for the treatment of chronic immune thrombocytopenia.

Authors:  Hanny Al-Samkari; David J Kuter
Journal:  Br J Clin Pharmacol       Date:  2018-08-13       Impact factor: 4.335

Review 5.  Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges.

Authors:  Shuaibo Huang; Nikolaos G Frangogiannis
Journal:  Br J Pharmacol       Date:  2018-03-04       Impact factor: 8.739

6.  PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial-mesenchymal transition.

Authors:  Siming Yu; Linna Li; Wei Tian; Dan Nie; Wei Mu; Fang Qiu; Yu Liu; Xinghan Liu; Xiaofeng Wang; Zhimin Du; Wen-Feng Chu; Baofeng Yang
Journal:  Br J Pharmacol       Date:  2018-06-15       Impact factor: 8.739

Review 7.  Hydrogen sulfide and dermatological diseases.

Authors:  Silvia A Coavoy-Sánchez; Soraia K P Costa; Marcelo N Muscará
Journal:  Br J Pharmacol       Date:  2019-06-18       Impact factor: 8.739

8.  Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice.

Authors:  Fabio Arturo Iannotti; Ester Pagano; Aniello Schiano Moriello; Filomena Grazia Alvino; Nicolina Cristina Sorrentino; Luca D'Orsi; Elisabetta Gazzerro; Raffaele Capasso; Elvira De Leonibus; Luciano De Petrocellis; Vincenzo Di Marzo
Journal:  Br J Pharmacol       Date:  2018-09-09       Impact factor: 8.739

9.  The ellagitannin metabolite urolithin C is a glucose-dependent regulator of insulin secretion through activation of L-type calcium channels.

Authors:  Morgane Bayle; Jérémie Neasta; Margherita Dall'Asta; Guillaume Gautheron; Anne Virsolvy; Jean-François Quignard; Estelle Youl; Richard Magous; Jean-François Guichou; Alan Crozier; Daniele Del Rio; Gérard Cros; Catherine Oiry
Journal:  Br J Pharmacol       Date:  2019-10-10       Impact factor: 8.739

10.  Successful treatment of established heart failure in mice with recombinant HDL (Milano).

Authors:  Joseph Pierre Aboumsallem; Mudit Mishra; Ruhul Amin; Ilayaraja Muthuramu; Herman Kempen; Bart De Geest
Journal:  Br J Pharmacol       Date:  2018-09-19       Impact factor: 8.739
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