THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Catalytic receptors

1The authors state that there are no conflicts of interest to declare.

2Catalytic 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.

3Amongst 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.

4A 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.

5S226 Cytokine receptor family

6S227 IL‐2 receptor family

7S228 IL‐3 receptor family

8S229 IL‐6 receptor family

9S231 IL‐12 receptor family

10S232 Prolactin receptor family

11S232 Interferon receptor family

12S233 IL‐10 receptor family

13S234 Immunoglobulin‐like family of IL‐1 receptors

14S235 IL‐17 receptor family

15S236 GDNF receptor family

16S237 Integrins

17S241 Natriuretic peptide receptor family

18S242 Pattern recognition receptors

19S242 Toll‐like receptor family

20S244 NOD‐like receptor family

21Ű RIG‐I‐like receptor family

22Ű Receptor kinases

23Ű TK: Tyrosine kinase

24S246 Receptor tyrosine kinases (RTKs)

25S246 Type I RTKs: ErbB (epidermal growth factor) receptor family

26S247 Type II RTKs: Insulin receptor family

27S248 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family

28S250 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

29S250 Type V RTKs: FGF (fibroblast growth factor) receptor family

30S251 Type VI RTKs: PTK7/CCK4

31S252 Type VII RTKs: Neurotrophin receptor/Trk family

32S253 Type VIII RTKs: ROR family

33S253 Type IX RTKs: MuSK

34S254 Type X RTKs: HGF (hepatocyte growth factor) receptor family

35S255 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family

36S255 Type XII RTKs: TIE family of angiopoietin receptors

37S256 Type XIII RTKs: Ephrin receptor family

38S256 Type XIV RTKs: RET

39S257 Type XV RTKs: RYK

40S258 Type XVI RTKs: DDR (collagen receptor) family

41S258 Type XVII RTKs: ROS receptors

42S258 Type XVIII RTKs: LMR family

43S259 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

44S260 Type XX RTKs: STYK1

45Ű TKL: Tyrosine kinase‐like

46S260 Receptor serine/threonine kinase (RSTK) fam‐ily

47S261 Type I receptor serine/threonine kinases

48S261 Type II receptor serine/threonine kinases

49S262 Type III receptor serine/threonine kinases

50S262 RSTK functional heteromers

51S264 Receptor tyrosine phosphatase (RTP) family

52S265 Tumour necrosis factor (TNF) receptor family

53Cytokines are not a clearly defined group of agents, other than having an impact on immune signalling pathways, although many cytokines have effects on other systems, such as in development. A feature of some cytokines, which allows them to be distinguished from hormones, is that they may be produced by “non‐secretory” cells, for example, endothelial cells. Within the cytokine receptor family, some subfamilies may be identified, which are described elsewhere in the Guide to PHARMACOLOGY, receptors for the TNF family, the TGF‐β family and the chemokines. Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. These receptors possess a conserved extracellular region, known as the cytokine receptor homology domain (CHD), along with a range of other structural modules, including extracellular immunoglobulin (Ig)‐like and fibronectin type III (FBNIII)‐like domains, a transmembrane domain, and intracellular homology domains. An unusual feature of this group of agents is the existence of soluble and decoy receptors. These bind cytokines without allowing signalling to occur. A further attribute is the production of endogenous antagonist molecules, which bind to the receptors selectively and prevent signalling. A commonality of these families of receptors is the ligand‐induced homo‐ or hetero‐oligomerisation, which results in the recruitment of intracellular protein partners to evoke cellular responses, particularly in inflammatory or haematopoietic signalling. Although not an exclusive signalling pathway, a common feature of the majority of cytokine receptors is activation of the JAK/STAT pathway. This cascade is based around the protein tyrosine kinase activity of the Janus kinases (JAK), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo‐ or heterodimeric STATs function principally as transcription factors in the nucleus.

54Type 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.

55Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif.

56The 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].

57The 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.

58The 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.

59Ho, LJ et al. (2015) Biological effects of interleukin‐6: Clinical applications in autoimmune diseases and cancers. Biochem Pharmacol 97: 16‐26 [PMID:26080005]

60Rothaug, M et al. (2016) The role of interleukin‐6 signaling in nervous tissue. Biochim Biophys Acta 1863: 1218‐27 [PMID:27016501]

61IL‐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.

62Prolactin family receptors form homodimers in the presence of their respective ligands, associate exclusively with Jak2 and signal via Stat5.

63Cabrera‐Reyes, EA et al. (2017) Prolactin function and putative expression in the brain. Endocrine [PMID:28634745]

64Goffin, V. (2017) Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge. Pharmacol Ther [PMID:28549597]

65The 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).

66Kotenko, SV et al. (2017) Contribution of type III interferons to antiviral immunity: location, location, location. J Biol Chem 292: 7295‐7303 [PMID:28289095]

67Ng, CT, et al. (2016) Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes. Cell 164: 349‐52 [PMID:26824652]

68Schreiber, G. (2017) The molecular basis for differential type I interferon signaling. J Biol Chem 292: 7285‐7294 [PMID:28289098]

69The 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).

70Felix J et al. (2017) Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat. Rev. Immunol. 17: 112‐129 [PMID:28028310]

71The 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.

72:

73The IL17 cytokine family consists of six ligands (IL‐17A‐F), which signal through five receptors (IL‐17RA‐E).

74Beringer, A et al. (2016) IL‐17 in Chronic Inflammation: From Discovery to Targeting. Trends Mol Med 22: 230‐41 [PMID:26837266]

75Lubberts, E. (2015) The IL‐23‐IL‐17 axis in inflammatory arthritis. Nat Rev Rheumatol 11: 415‐29 [PMID:25907700]

76GDNF 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).

77Inhibitors 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.

78Allen SJ et al. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138: 155‐75 [PMID:23348013]

79Ibanez 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]

80Merighi 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]

81Integrins 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.

82Integrins 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.

83Collagen 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)).

84Laminin 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.

85fibrinogen(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.

86fibronectin(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.

87vitronectin(VTN, P04004) is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide ‐linked dimer.

88osteopontin(SPP1, P10451) forms an integral part of the mineralized matrix in bone, where it undergoes extensive post‐translation processing, including proteolysis and phosphorylation.

89von 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).

90Clemetson, KJ. (2017) The origins of major platelet receptor nomenclature. Platelets 28: 40‐42 [PMID:27715379]

91Hamidi, H et al. (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer 115: 1017‐1023 [PMID:27685444]

92Horton, ER et al. (2016) The integrin adhesome network at a glance. J Cell Sci 129: 4159‐4163 [PMID:27799358]

93Ley, K et al. (2016) Integrin‐based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15: 173‐83 [PMID:26822833]

94Manninen, A et al. (2017) A proteomics view on integrin‐mediated adhesions. Proteomics 17: [PMID:27723259]

95Park, YK et al. (2016) Integrins in synapse regulation. Nat Rev Neurosci 17: 745‐756 [PMID:27811927]

96Natriuretic 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].

97The 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.

98Blomain, ES et al. (2016) Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer. Mol Pharmacol 90: 199‐204 [PMID:27251363]

99Kuhn, M. (2016) Molecular Physiology of Membrane Guanylyl Cyclase Receptors. Physiol Rev 96: 751‐804 [PMID:27030537]

100Santhekadur, PK et al. (2017) The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed Pharmacother 92: 826‐835 [PMID:28599248]

101Theilig, F et al. (2015) ANP‐induced signaling cascade and its implications in renal pathophysiology. Am J Physiol Renal Physiol 308: F1047‐55 [PMID:25651559]

102Volpe, 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]

103Pattern 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.

104PRRs included in the Guide To PHARMACOLOGY are:

105Catalytic PRRs (see links below this overview)

106Toll‐like receptors (TLRs)

107Nucleotide‐binding oligomerization domain‐like receptors (NLRs, also known as NOD‐like receptors)

108RIG‐I‐like receptors (RLRs)

109Absent in melanoma (AIM)‐like receptors (ALRs)

110C‐type lectin‐like receptors (CLRs), and

111Other pattern recognition receptors.

112Members 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].

113Bryant 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]

114Goulopoulou S et al. (2016) Toll‐like Receptors in the Vascular System: Sensing the Dangers Within. Pharmacol Rev 68: 142‐67 [PMID:26721702]

115Micera A et al. (2016) Toll‐Like Receptors and Tissue Remodeling: The Pro/Cons Recent Findings. J Cell Physiol 231: 531‐44 [PMID:26248215]

116Zhang Z et al. (2017) Towards a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system. FEBS Lett [PMID:28686285]

117Zinngrebe J et al. (2017) TLRs Go Linear ‐ On the Ubiquitin Edge. Trends Mol Med 23: 296‐309 [PMID:28325627]

118The 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).

119Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase RIPK2(receptor interacting serine/threonine kinase 2, O43353, also known as CARD3, CARDIAK, RICK, RIP2) leading to signalling through NFκB and MAP kinase. Activation of NLRC4 (previously known as IPAF) and members of the NLRP3 family, including NLRP1 and NLRP3, leads to formation of a large multiprotein complex known as the inflammasome. In addition to NLR proteins other key members of the inflammasome include the adaptor protein ASC (apoptosis‐associated speck‐like protein containing a CARD, also known as PYCARD, CARD5, TMS1, Q9ULZ3) and inflammatory caspases. The inflammasome activates the pro‐inflammatory cytokines IL‐1β(IL1B, P01584) and IL‐18(IL18, Q14116) [16, 32].

120NLRP3 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 β(APP, P05067) [161].

121Loss‐of‐function mutations of NLRP3 are associated with cold autoinflammatory and Muckle‐Wells syndromes.

122This 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.

123Bryant 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]

124Kong X et al. (2017) The function of NOD‐like receptors in central nervous system diseases. J Neurosci Res 95: 1565‐1573 [PMID:28029680]

125Motta V et al. (2015) NOD‐like receptors: versatile cytosolic sentinels. Physiol Rev 95: 149‐78 [PMID:25540141]

126Receptor 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].

127All RTKs display an extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity (occasionally split into two domains by an insertion, termed the kinase insertion), with juxta‐membrane and C‐terminal regulatory regions. Agonist binding to the extracellular domain evokes dimerization, and sometimes oligomerization, of RTKs (a small subset of RTKs forms multimers even in the absence of activating ligand). This leads to autophosphorylation in the tyrosine kinase domain in a trans orientation, serving as a site of assembly of protein complexes and stimulation of multiple signal transduction pathways, including phospholipase C‐γ, mitogen‐activated protein kinases and phosphatidylinositol 3‐kinase [184].

128RTKs 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.

129ErbB 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.

130[125I]EGF (human) has been used to label the ErbB1 EGF receptor. The extracellular domain of ErbB2 can be targetted by the antibodies trastuzumab and pertuzumab to inhibit ErbB family action. The intracellular ATP‐binding site of the tyrosine kinase domain can be inhibited by GW583340(7.9–8.0, [50]), gefitinib, erlotinib and tyrphostins AG879 and AG1478.

131Kobayashi Y et al. (2016) Not all EGFR mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. [PMID:27323238]

132The 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).

133Serum 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.

134There 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.

135Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.

136PQ401 inhibits the insulin‐like growth factor receptor [5], while BMS‐536924 inhibits both the insulin receptor and the insulin‐like growth factor receptor [197].

137Type 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.

138Various 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].

139VEGF 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.

140The 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.

141Fibroblast 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].

142Splice variation of the receptors can influence agonist responses. FGFRL1(Q8N441) is a truncated kinase‐null analogue.

143Various 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].

144The 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].

145Thus far, no selective PTK7 inhibitors have been described.

146The 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.

147[125I]NGF (human) and [125I]BDNF (human) have been used to label the trkA and trkB receptor, respectively. p75 influences the binding of NGF(NGF, P01138) and neurotrophin‐3(NTF3, P20783) to trkA. The ligand selectivity of p75 appears to be dependent on the cell type; for example, in sympathetic neurones, it binds neurotrophin‐3(NTF3, P20783) with comparable affinity to trkC [35].

148Small 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].

149Members 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].

150The 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].

151Thus far, no selective MuSK inhibitors have been described.

152HGF 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.

153PF04217903 is a selective Met tyrosine kinase inhibitor [29]. SU11274 is an inhibitor of the HGF receptor [185], with the possibility of further targets [5].

154Members 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.

155AXL tyrosine kinase inhibitors have been described [131].

156The 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.

157Ephrin 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.

158Ret 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.

159A number of tyrosine kinase inhibitors targeting RET have been described [43].

160The ‘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].

161Thus far, no selective RYK inhibitors have been described.

162Discoidin 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).

163The 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).

164crizotinib is a tyrosine kinase inhibitor, anti‐cancer drug targeting ALK and ROS1.

165The 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].

166As yet no selective inhibitors of the LMR family have been described.

167The 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].

168Similar 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].

169As yet, no selective inhibitors of STYK1 have been described.

170Alvarez‐Aznar A et al. (2017) VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function. Curr Top Dev Biol 123: 433‐482 [PMID:28236974]

171Bergeron 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]

172Carvalho 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]

173De Silva DM et al. (2017) Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem Soc Trans [PMID:28673936]

174Eklund, L et al. (2017) Angiopoietin‐Tie signalling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 131 87‐103 [PMID:27941161]

175Katayama, R. (2017) Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)‐rearranged lung cancer. Pharmacol Ther [PMID:28185914]

176Kazlauskas, A. (2017) PDGFs and their receptors. Gene 614 1‐7 [PMID:28267575]

177Ke, 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]

178Kuwano, M et al. (2016) Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol Ther 161: 97‐110 [PMID:27000770]

179Lee, 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]

180Nelson, KN et al. (2017) Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. Trends Mol Med 23: 59‐79 [PMID:27988109]

181Simons M et al. (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17: 611‐25 [PMID:27461391]

182Stricker S et al. (2017) ROR‐Family Receptor Tyrosine Kinases. Curr Top Dev Biol 123: 105‐142 [PMID:28236965]

183Tan, AC et al. (2017) Exploiting receptor tyrosine kinase co‐activation for cancer therapy. Drug Discov Today 22: 72‐84 [PMID:27452454]

184Receptor 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.

185Endogenous 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.

186The 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).

187For the receptors listed on this page, the exact combination of subunits forming the functional heteromeric receptors is unknown.

188Comments on Receptor serine/threonine kinase (RSTK) family: A number of endogenous inhibitory ligands have been identified for RSTKs, including BMP‐3(BMP3, P12645), inhibin α(INHA, P05111), inhibin βC(INHBC, P55103) and inhibin βE(INHBE, P58166).

189An 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].

190Smads 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.

191Budi EH et al. (2017) Transforming Growth Factor‐beta Receptors and Smads: Regulatory Complexity and Functional Versatility. Trends Cell Biol [PMID:28552280]

192Chen W et al. (2016) Immunoregulation by members of the TGFbeta superfamily. Nat Rev Immunol 16: 723‐740 [PMID:27885276]

193Heger J. (2016) Molecular switches under TGFbeta signalling during progression from cardiac hypertrophy to heart failure. Br J Pharmacol 173: 3‐14 [PMID:26431212]

194Luo JY et al. (2015) Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system. J Physiol 593: 2995‐3011 [PMID:25952563]

195Macias MJ et al. (2015) Structural determinants of Smad function in TGF‐beta signaling. Trends Biochem Sci 40: 296‐308 [PMID:25935112]

196Morrell NW et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 13: 106‐20 [PMID:26461965]

197Neuzillet C et al. (2015) Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther 147: 22‐31 [PMID:25444759]

198van der Kraan PM. (2017) The changing role of TGFbeta in healthy, ageing and osteoarthritic joints. Nat Rev Rheumatol 13: 155‐163 [PMID:28148919]

199Receptor 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.

200He R et al. (2013) Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J. 280: 731‐50 [PMID:22816879]

201Papadimitriou 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]

202Stanford SM et al. (2017) Targeting Tyrosine Phosphatases: Time to End the Stigma. Trends Pharmacol Sci 38: 524‐540 [PMID:28412041]

203The 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.

204TNFRSF1A 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).

205Blaser H et al. (2016) TNF and ROS Crosstalk in Inflammation. Trends Cell Biol 26: 249‐61 [PMID:26791157]

206Croft 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]

207Kalliolias GD et al. (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12: 49‐62 [PMID:26656660]

208Olesen CM et al. (2016) Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol Ther 159: 110‐9 [PMID:26808166]

209von Karstedt S et al. (2017) Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer 17: 352‐366 [PMID:28536452]