THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Catalytic receptors

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

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.

5S248 Cytokine receptor family

6S249 IL‐2 receptor family

7S251 IL‐3 receptor family

8S252 IL‐6 receptor family

9S254 IL‐12 receptor family

10S255 Prolactin receptor family

11S256 Interferon receptor family

12S257 IL‐10 receptor family

13S258 Immunoglobulin‐like family of IL‐1 receptors

14S259 IL‐17 receptor family

15S259 GDNF receptor family

16S260 Integrins

17S264 Pattern recognition receptors

18S264 Toll‐like receptor family

19S266 NOD‐like receptor family

20S268 RIG‐I‐like receptor family

21S269 Receptor guanylyl cyclase (RGC) family

22S269 Transmembrane guanylyl cyclases

23S270 Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclase

24– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=699

25– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=686

26S271 Receptor tyrosine kinases (RTKs)

27S272 Type I RTKs: ErbB (epidermal growth factor) receptor family

28S273 Type II RTKs: Insulin receptor family

29S274 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family

30S275 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

31S275 Type V RTKs: FGF (fibroblast growth factor) receptor family

32S276 Type VI RTKs: PTK7/CCK4

33S277 Type VII RTKs: Neurotrophin receptor/ Trk family

34S278 Type VIII RTKs: ROR family

35S278 Type IX RTKs: MuSK

36S279 Type X RTKs: HGF (hepatocyte growth factor) receptor family

37S279 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family

38S280 Type XII RTKs: TIE family of angiopoietin receptors

39S280 Type XIII RTKs: Ephrin receptor family

40S281 Type XIV RTKs: RET

41S282 Type XV RTKs: RYK

42S282 Type XVI RTKs: DDR (collagen receptor) family

43S283 Type XVII RTKs: ROS receptors

44S283 Type XVIII RTKs: LMR family

45S284 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

46S284 Type XX RTKs: STYK1

47– http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=687

48S286 Receptor serine/threonine kinase (RSTK) family

49S286 Type I receptor serine/threonine kinases

50S287 Type II receptor serine/threonine kinases

51S287 Type III receptor serine/threonine kinases

52S287 RSTK functional heteromers

53S289 Receptor tyrosine phosphatase (RTP) family

54S291 Tumour necrosis factor (TNF) receptor family

55Cytokines 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=334, the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=303 family and the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=14. 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.

56Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif.

57The IL‐2 receptor family consists of one or more ligand‐selective subunits, and a common γ chain (γc): IL2RG, http://www.uniprot.org/uniprot/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 [211].

58Leonard WJ et al. (2019) The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications Immunity 50: 832‐850

59The IL‐3 receptor family signal through a receptor complex comprising of a ligand‐specific α subunit and a common β chain (CSF2RB, http://www.uniprot.org/uniprot/P32927), which is associated with Jak2 and signals primarily through Stat5.

60The IL‐6 receptor family signal through a ternary receptor complex consisting of the cognate receptor and either the IL‐6 signal transducer gp130 (IL6ST, http://www.uniprot.org/uniprot/P40189) or the oncostatin M‐specific receptor, β subunit (OSMR, http://www.uniprot.org/uniprot/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.

61Ho LJ et al. (2015) Biological effects of interleukin‐6: Clinical applications in autoimmune diseases and cancers. Biochem. Pharmacol. 97: 16‐26 https://www.ncbi.nlm.nih.gov/pubmed/26080005?dopt=AbstractPlus

62Kang S et al. (2019) Targeting Interleukin‐6 Signaling in Clinic Immunity 50: 1007‐1023

63Murakami M et al. (2019) Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines Immunity 50: 812‐831

64Rothaug M et al. (2016) The role of interleukin‐6 signaling in nervous tissue. Biochim. Biophys. Acta 1863: 1218‐27 https://www.ncbi.nlm.nih.gov/pubmed/27016501?dopt=AbstractPlus

65IL‐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.

66Wojno EDT et al. (2019) The Immunobiology of the Interleukin‐12 Family: Room for Discovery Immunity 50: 851‐870

67Prolactin family receptors form homodimers in the presence of their respective ligands, associate exclusively with Jak2 and signal via Stat5.

68Cabrera‐Reyes EA et al. (2017) Prolactin function and putative expression in the brain. Endocrine 57: 199‐213 https://www.ncbi.nlm.nih.gov/pubmed/28634745?dopt=AbstractPlus

69Goffin V. (2017) Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge. Pharmacol. Ther. 179: 111‐126 https://www.ncbi.nlm.nih.gov/pubmed/28549597?dopt=AbstractPlus

70The 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, http://www.uniprot.org/uniprot/P01562), α2 (IFNA2, http://www.uniprot.org/uniprot/P01563), α4 (IFNA4, http://www.uniprot.org/uniprot/P05014), α5 (IFNA5, http://www.uniprot.org/uniprot/P01569), α6 (IFNA6, http://www.uniprot.org/uniprot/P05013), α7 (IFNA7, http://www.uniprot.org/uniprot/P01567), α8 (IFNA8, http://www.uniprot.org/uniprot/P32881), α10 (IFNA10, http://www.uniprot.org/uniprot/P01566), α13 (IFNA13, http://www.uniprot.org/uniprot/P01562), α14 (IFNA14, http://www.uniprot.org/uniprot/P01570), α16 (IFNA16, http://www.uniprot.org/uniprot/P05015), α17 (IFNA17, http://www.uniprot.org/uniprot/P01571) and α21 (IFNA21, http://www.uniprot.org/uniprot/P01568).

71Kotenko SV et al. (2017) Contribution of type III interferons to antiviral immunity: location, location, location. J. Biol. Chem. 292: 7295‐7303 https://www.ncbi.nlm.nih.gov/pubmed/28289095?dopt=AbstractPlus

72Lazear HM et al. (2019) Shared and Distinct Functions of Type I and Type III Interferons Immunity 50: 907‐923

73Ng CT et al. (2016) Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes. Cell 164: 349‐52 https://www.ncbi.nlm.nih.gov/pubmed/26824652?dopt=AbstractPlus

74Schreiber G. (2017) The molecular basis for differential type I interferon signaling. J. Biol. Chem. 292: 7285‐7294 https://www.ncbi.nlm.nih.gov/pubmed/28289098?dopt=AbstractPlus

75The 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).

76Felix J et al. (2017) Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat. Rev. Immunol. 17: 112‐129 https://www.ncbi.nlm.nih.gov/pubmed/28028310?dopt=AbstractPlus

77Ouyang W et al. (2019) IL‐10 Family Cytokines IL‐10 and IL‐22: from Basic Science to Clinical Translation Immunity 50: 871‐891

78The immunoglobulin‐like family of IL‐1 receptors are heterodimeric receptors made up of a cognate receptor subunit and an IL‐1 receptor accessory protein, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5995 (http://www.uniprot.org/uniprot/Q9NPH3, also known as C3orf13, IL‐1RAcP, IL1R3). They are characterised by extracellular immunoglobulin‐like domains and an intracellular Toll/Interleukin‐1R (TIR) domain.

79Afonina IS et al. (2015) Proteolytic Processing of Interleukin‐1 Family Cytokines: Variations on a Common Theme. Immunity 42: 991‐1004 https://www.ncbi.nlm.nih.gov/pubmed/26084020?dopt=AbstractPlus

80Mantovani A et al. (2019) Interleukin‐1 and Related Cytokines in the Regulation of Inflammation and Immunity Immunity 50: 778‐795

81The IL17 cytokine family consists of six ligands (IL‐17A‐F), which signal through five receptors (IL‐17RA‐E).

82Beringer A et al. (2016) IL‐17 in Chronic Inflammation: From Discovery to Targeting. Trends Mol Med 22: 230‐241 https://www.ncbi.nlm.nih.gov/pubmed/26837266?dopt=AbstractPlus

83Lubberts E. (2015) The IL‐23‐IL‐17 axis in inflammatory arthritis. Nat Rev Rheumatol 11: 415‐29 https://www.ncbi.nlm.nih.gov/pubmed/25907700?dopt=AbstractPlus

84McGeachy MJ et al. (2019) The IL‐17 Family of Cytokines in Health and Disease Immunity 50: 892‐906

85GDNF 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, https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9967 (see http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=304). The endogenous ligands are typically dimeric, linked through disulphide bridges: glial cell‐derived neurotrophic factor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4940 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4232, http://www.uniprot.org/uniprot/P39905) (211 aa); http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5032 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8007, http://www.uniprot.org/uniprot/Q99748) (197 aa); http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4871 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:727, http://www.uniprot.org/uniprot/Q5T4W7) (237 aa) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5045 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9579, http://www.uniprot.org/uniprot/O60542) (PSPN, 156 aa).

86Inhibitors of other receptor tyrosine kinases, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5056, which inhibits VEGF receptor function, may also inhibit Ret function [http://www.ncbi.nlm.nih.gov/pubmed/17032739?dopt=AbstractPlus]. 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.

87Allen SJ et al. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138: 155‐75 https://www.ncbi.nlm.nih.gov/pubmed/23348013?dopt=AbstractPlus

88Ibáñez CF et al. (2017) Biology of GDNF and its receptors ‐ Relevance for disorders of the central nervous system. Neurobiol. Dis. 97: 80‐89 https://www.ncbi.nlm.nih.gov/pubmed/26829643?dopt=AbstractPlus

89Merighi A. (2016) Targeting the glial‐derived neurotrophic factor and related molecules for controlling normal and pathologic pain. Expert Opin. Ther. Targets 20: 193‐208 https://www.ncbi.nlm.nih.gov/pubmed/26863504?dopt=AbstractPlus

90Integrins 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.

91Integrins 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 a 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 outsidein signalling.

92Several drugs that target integrins are in clinical use including: (1) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6584 (αIIbβ3) for short term prevention of coronary thrombosis, (2) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7437 (α4β7) to reduce gastrointestinal inflammation, and (3) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6591 (α4β1) in some cases of severe multiple sclerosis.

93Collagen 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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4898 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2197, http://www.uniprot.org/uniprot/P02452)) and collagen II (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4899 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2200, http://www.uniprot.org/uniprot/P02458)).

94Laminin 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.

95http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6749 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3661 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3662 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3694, http://www.uniprot.org/uniprot/P02671 http://www.uniprot.org/uniprot/P02675 http://www.uniprot.org/uniprot/P02679) is a glycosylated hexamer composed of two α (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3661, http://www.uniprot.org/uniprot/P02671), two β (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3662, http://www.uniprot.org/uniprot/P02675) and two γ (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3694, http://www.uniprot.org/uniprot/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.

96http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6754 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3778, http://www.uniprot.org/uniprot/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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3778, http://www.uniprot.org/uniprot/P02751) generates multiple isoforms.

97http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6746 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12724, http://www.uniprot.org/uniprot/P04004) is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide ‐linked dimer.

98http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6753 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11255, http://www.uniprot.org/uniprot/P10451) forms an integral part of the mineralized matrix in bone, where it undergoes extensive posttranslation processing, including proteolysis and phosphorylation.

99http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6755 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12726, http://www.uniprot.org/uniprot/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).

100Clemetson KJ. (2017) The origins of major platelet receptor nomenclature. Platelets 28: 40‐42 https://www.ncbi.nlm.nih.gov/pubmed/27715379?dopt=AbstractPlus

101Emsley J et al. (2000) Structural basis of collagen recognition by integrin alpha2beta1. Cell 101: 47‐56 https://www.ncbi.nlm.nih.gov/pubmed/10778855?dopt=AbstractPlus

102Hamidi H et al. (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer 115: 1017‐1023 https://www.ncbi.nlm.nih.gov/pubmed/27685444?dopt=AbstractPlus

103Horton ER et al. (2016) The integrin adhesome network at a glance. J. Cell. Sci. 129: 4159‐4163 https://www.ncbi.nlm.nih.gov/pubmed/27799358?dopt=AbstractPlus

104Ley K et al. (2016) Integrin‐based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 15: 173‐83 https://www.ncbi.nlm.nih.gov/pubmed/26822833?dopt=AbstractPlus

105Manninen A et al. (2017) A proteomics view on integrin‐mediated adhesions. Proteomics 17: https://www.ncbi.nlm.nih.gov/pubmed/27723259?dopt=AbstractPlus

106Raab‐Westphal S et al. (2017) Integrins as Therapeutic Targets: Successes and Cancers. Cancers (Basel) 9: https://www.ncbi.nlm.nih.gov/pubmed/28832494?dopt=AbstractPlus

107Pattern Recognition Receptors (PRRs, [http://www.ncbi.nlm.nih.gov/pubmed/20303872?dopt=AbstractPlus]) (nomenclature as agreed by NC‐IUPHAR sub‐committee on Pattern Recognition Receptors, [http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) 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 or endogenous ligands, termed DAMPS or damage‐associated molecular patterns. These include 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 of IL‐1β cleavage and secretion, and others in the initiation of the type I interferon response.

108PRRs included in the Guide To PHARMACOLOGY are:

109Catalytic PRRs (see links below this overview)

110Toll‐like receptors (TLRs)

111Nucleotide‐binding oligomerization domain, leucine‐rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)‐like receptors)

112RIG‐I‐like receptors (RLRs)

113http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1620 and http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1621

114Non‐catalytic PRRs

115http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=942 (ALRs)

116http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=945

117http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=929

118http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2843 (RAGE)

119Members of the toll‐like family of receptors (nomenclature recommended by the NC‐IUPHAR subcommittee on pattern recognition receptors, [http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) 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, [http://www.ncbi.nlm.nih.gov/pubmed/11431423?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12077222?dopt=AbstractPlus]). 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4953 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5261, http://www.uniprot.org/uniprot/P10809) [http://www.ncbi.nlm.nih.gov/pubmed/10623794?dopt=AbstractPlus].

120Anthoney N et al. (2018) Toll and Toll‐like receptor signalling in development. Development 145: https://www.ncbi.nlm.nih.gov/pubmed/29695493?dopt=AbstractPlus

121Bryant CE et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 https://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus

122Franz KM et al. (2017) Innate Immune Receptors as Competitive Determinants of Cell Fate. Mol. Cell 66: 750‐760 https://www.ncbi.nlm.nih.gov/pubmed/28622520?dopt=AbstractPlus

123Joosten LA et al. (2016) Toll‐like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol 12: 344‐57 https://www.ncbi.nlm.nih.gov/pubmed/27170508?dopt=AbstractPlus

124Nunes KP et al. (2018) Targeting toll‐like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension? Br. J. Pharmacol. https://www.ncbi.nlm.nih.gov/pubmed/29981161?dopt=AbstractPlus

125Zhang Z et al. (2017) Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system. FEBS Lett. 591: 3167‐3181 https://www.ncbi.nlm.nih.gov/pubmed/28686285?dopt=AbstractPlus

126The nucleotide‐binding oligomerization domain, leucine‐rich repeat (NLR) family of receptors (nomenclature recommended by the NC‐IUPHAR subcommittee on pattern recognition receptors [http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) share a common domain organisation. This consists of an N‐terminal effector domain, a central nucleotidebinding 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 [http://www.ncbi.nlm.nih.gov/pubmed/18341998?dopt=AbstractPlus]. NLRC members express an N‐terminal caspase recruitment domain (CARD) and NLRP members an N‐terminal Pyrin domain (PYD).

127Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2190 (receptor interacting serine/threonine kinase 2, http://www.uniprot.org/uniprot/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, http://www.uniprot.org/uniprot/Q9ULZ3) and inflammatory caspases. The inflammasome activates the pro‐inflammatory cytokines http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4974 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5992, http://www.uniprot.org/uniprot/P01584) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4983 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5986, http://www.uniprot.org/uniprot/Q14116) [http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21219188?dopt=AbstractPlus]

128NLRP3 has also been reported to respond to hostderived products, known as danger‐associated molecular patterns, or DAMPs, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4731 [http://www.ncbi.nlm.nih.gov/pubmed/16407889?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4719, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4954 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4865 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:620, http://www.uniprot.org/uniprot/P05067) [http://www.ncbi.nlm.nih.gov/pubmed/20303873?dopt=AbstractPlus].

129Loss‐of‐function mutations of NLRP3 are associated with cold autoinflammatory and Muckle‐Wells syndromes.

130This family also includes http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2793 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7634, http://www.uniprot.org/uniprot/Q13075) which can be found in the ‘Inhibitors of apoptosis (IAP) protein family’ in the http://www.guidetopharmacology.org/GRAC/ReceptorFamiliesForward?type=OTHER section of the Guide.

131Broz P et al. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16: 407‐20 https://www.ncbi.nlm.nih.gov/pubmed/27291964?dopt=AbstractPlus

132Bryant CE et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462‐504 https://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus

133Keestra‐Gounder AM et al. (2017) NOD1 and NOD2: Beyond Peptidoglycan Sensing. Trends Immunol. 38: 758‐767 https://www.ncbi.nlm.nih.gov/pubmed/28823510?dopt=AbstractPlus

134Lei‐Leston AC et al. (2017) Epithelial Cell Inflammasomes in Intestinal Immunity and Inflammation. Front Immunol 8: 1168 https://www.ncbi.nlm.nih.gov/pubmed/28979266?dopt=AbstractPlus

135Man SM. (2018) Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. Nat Rev Gastroenterol Hepatol 15: 721‐737 https://www.ncbi.nlm.nih.gov/pubmed/30185915?dopt=AbstractPlus

136Mukherjee T et al. (2018) NOD1 and NOD2 in inflammation, immunity and disease. Arch. Biochem. Biophys. https://www.ncbi.nlm.nih.gov/pubmed/30578751?dopt=AbstractPlus

137Nielsen AE et al. (2017) Synthetic agonists of NOD‐like, RIG‐I‐like, and C‐type lectin receptors for probing the inflammatory immune response. Future Med Chem 9: 1345‐1360 https://www.ncbi.nlm.nih.gov/pubmed/28776416?dopt=AbstractPlus

138There are three human RIG‐I‐like receptors (RLRs) which are cytoplasmic pattern recognition receptors (PRRs) of the innate immune system. They detect non‐self cytosolic double‐stranded RNA species and and 5′‐triphosphate single‐stranded RNA from various sources and are essential for inducing production of type I interferons, such as IFNβ, type III interferons, and other anti‐pathogenic effectors [http://www.ncbi.nlm.nih.gov/pubmed/25081315?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]. They function as RNA helicases (EC 3.6.4.13) using the energy from ATP hydrolysis to unwind RNA.

139Chow KT et al. (2018) RIG‐I and Other RNA Sensors in Antiviral Immunity. Annu. Rev. Immunol. 36: 667–694 https://www.ncbi.nlm.nih.gov/pubmed/29677479?dopt=AbstractPlus

140Kato H et al. (2015) RIG‐I‐like receptors and autoimmune diseases. Curr. Opin. Immunol. 37: 40–5 https://www.ncbi.nlm.nih.gov/pubmed/26530735?dopt=AbstractPlus

141Lässig C et al. (2017) Discrimination of cytosolic self and non‐self RNA by RIG‐I‐like receptors. J. Biol. Chem. 292: 9000‐9009 https://www.ncbi.nlm.nih.gov/pubmed/28411239?dopt=AbstractPlus

142Ma Z et al. (2018) Innate Sensing of DNA Virus Genomes. Annu Rev Virol 5: 341–362 https://www.ncbi.nlm.nih.gov/pubmed/30265633?dopt=AbstractPlus

143Against Emerging and Re‐Emerging Viral Infections. Front Immunol 9: 1379 https://www.ncbi.nlm.nih.gov/pubmed/29973930?dopt=AbstractPlus

144Broz P et al. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16: 407–20 https://www.ncbi.nlm.nih.gov/pubmed/27291964?dopt=AbstractPlus

145Bryant CE et al. (2015) Advances in Toll‐like receptor biology: Modes of activation by diverse stimuli. Crit. Rev. Biochem. Mol. Biol. 50: 359–79 https://www.ncbi.nlm.nih.gov/pubmed/25857820?dopt=AbstractPlus

146Feerick CL et al. (2017) Understanding the regulation of pattern recognition receptors in inflammatory diseases ‐ a ‘Nod’ in the right direction. Immunology 150: 237–247 https://www.ncbi.nlm.nih.gov/pubmed/27706808?dopt=AbstractPlus

147Rathinam VA et al. (2016) Inflammasome Complexes: Emerging Mechanisms and Effector Functions. Cell 165: 792–800 https://www.ncbi.nlm.nih.gov/pubmed/27153493?dopt=AbstractPlus

148Unterholzner L. (2013) The interferon response to intracellular DNA: why so many receptors? Immunobiology 218: 1312–21 https://www.ncbi.nlm.nih.gov/pubmed/23962476?dopt=AbstractPlus

149Yin Q et al. (2015) Structural biology of innate immunity. Annu. Rev. Immunol. 33: 393–416 https://www.ncbi.nlm.nih.gov/pubmed/25622194?dopt=AbstractPlus

150The mammalian genome encodes transmembrane and soluble receptor guanylyl cyclases, both of which have enzyme activities which convert http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1742 to the intracellular second messenger cyclic guanosine‐3′,5′‐monophosphate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347).

151Transmembrane guanylyl cyclases are homodimeric receptors activated by a diverse range of endogenous ligands. GC‐A, GC‐B and GC‐C are expressed predominantly in the cardiovascular system, skeletal system and intestinal epithelium, respectively. GC‐D and GC‐G are found in the olfactory neuropepithelium and Grüeneberg ganglion of rodents, respectively. GC‐E and GC‐F are expressed in retinal photoreceptors. 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 Gproteins, to activation of phospholipase C, inwardly‐rectifying potassium channels and inhibition of adenylyl cyclase activity [http://www.ncbi.nlm.nih.gov/pubmed/10364194?dopt=AbstractPlus].

152The polysaccharide obtained from fermentation of Aureobasidium species, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4952, acts as an antagonist at both GC‐A and GC‐B receptor s [http://www.ncbi.nlm.nih.gov/pubmed/1674870?dopt=AbstractPlus]. GC‐D and GC‐G have been reported to be activated intracellularly by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9164 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4678, http://www.uniprot.org/uniprot/P43080) and guanylyl cyclaseactivating protein (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4679, https://www.uniprot.org/uniprot/Q9UMX6). GC‐D and GC‐G may be activated by atmospheric levels of CO2 through the formation of intracellular bicarbonate ions [http://www.ncbi.nlm.nih.gov/pubmed/20738256?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17702944?dopt=AbstractPlus]. GC‐G may be activated at cooler temperatures (20‐25°C) through apparent stabilisation of the dimer [http://www.ncbi.nlm.nih.gov/pubmed/25452496?dopt=AbstractPlus].

153Nitric oxide (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509)‐sensitive (soluble) guanylyl cyclase (GTP diphosphate‐lyase (cyclising)), http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=4.6.1.2, is a heterodimer comprising a β1 subunit and one of two alpha subunits (α1, α2) giving rise to two functionally indistinguishable isoforms, GC‐1 (α1β1) and GC‐2 (α2β1) [http://www.ncbi.nlm.nih.gov/pubmed/9742221?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/9742212?dopt=AbstractPlus]. A haem group is associated with the β subunit and is the target for the endogenous ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509, and, potentially, carbon monoxide [http://www.ncbi.nlm.nih.gov/pubmed/9003762?dopt=AbstractPlus].

154http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5234 also shows activity at other haem‐containing proteins [http://www.ncbi.nlm.nih.gov/pubmed/10419542?dopt=AbstractPlus], while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5291 may also inhibit cGMP‐hydrolysing phosphodiesterases [http://www.ncbi.nlm.nih.gov/pubmed/9855623?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/10369473?dopt=AbstractPlus].

155Kuhn M. (2016) Molecular Physiology of Membrane Guanylyl Cyclase Receptors. Physiol. Rev. 96: 751‐804 https://www.ncbi.nlm.nih.gov/pubmed/27030537?dopt=AbstractPlus

156Papapetropoulos A et al. (2015) Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS. Br. J. Pharmacol. 172: 1397–414 https://www.ncbi.nlm.nih.gov/pubmed/25302549?dopt=AbstractPlus

157Santhekadur PK et al. (2017) The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed. Pharmacother. 92: 826–835 https://www.ncbi.nlm.nih.gov/pubmed/28599248?dopt=AbstractPlus

158Vanhoutte PM et al. (2016) Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium‐Derived Vasodilator Mediator. Circ. Res. 119: 375‐96 https://www.ncbi.nlm.nih.gov/pubmed/27390338?dopt=AbstractPlus

159Volpe M et al. (2016) The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin. Sci. 130: 57–77 https://www.ncbi.nlm.nih.gov/pubmed/26637405?dopt=AbstractPlus

160Waldman SA et al. (2018) Guanylate cyclase‐C as a therapeutic target in gastrointestinal disorders. Gut 67: 1543–1552 https://www.ncbi.nlm.nih.gov/pubmed/29563144?dopt=AbstractPlus

161Receptor tyrosine kinases (RTKs), a family of cellsurface 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 [http://www.ncbi.nlm.nih.gov/pubmed/11357143?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17575237?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/2158859?dopt=AbstractPlus]. In the human genome, 58 RTKs have been identified, which fall into 20 families [http://www.ncbi.nlm.nih.gov/pubmed/20602996?dopt=AbstractPlus].

162All 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 juxtamembrane 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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=244, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=246#mitogen‐activated protein kinases and phosphatidylinositol 3‐kinase [http://www.ncbi.nlm.nih.gov/pubmed/2158859?dopt=AbstractPlus].

163RTKs 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 thatmodify 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.

164http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00500000269785 are Class I receptor tyrosine kinases [http://www.ncbi.nlm.nih.gov/pubmed/12520021?dopt=AbstractPlus]. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3430 (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 [http://www.ncbi.nlm.nih.gov/pubmed/9130710?dopt=AbstractPlus]. 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 inmany cancers, particularly forms of breast cancer and lung cancer. Mutations in the EGFR are responsible for acquired resistance to tyrosine kinase inhibitor chemotherapeutics.

165http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4848 has been used to label the ErbB1 EGF receptor. The extracellular domain of ErbB2 can be targetted by the antibodies http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5082 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5046 to inhibit ErbB family action. The intracellular ATP‐binding site of the tyrosine kinase domain can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4947 (7.9‐8.0, [http://www.ncbi.nlm.nih.gov/pubmed/12639547?dopt=AbstractPlus]), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4941, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4920 and tyrphostins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4863 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4862.

166Kobayashi Y et al. (2016) Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 107: 1179‐86 https://www.ncbi.nlm.nih.gov/pubmed/27323238?dopt=AbstractPlus

167The circulating peptide hormones http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5012 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6081, http://www.uniprot.org/uniprot/P01308) and the related insulin‐like growth factors (IGF) activate Class II receptor tyrosine kinases [http://www.ncbi.nlm.nih.gov/pubmed/12520021?dopt=AbstractPlus], 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 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6125 (http://www.uniprot.org/uniprot/P35568), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6126 (http://www.uniprot.org/uniprot/Q9Y4H2), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:10840 (http://www.uniprot.org/uniprot/P29353), https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4566 (http://www.uniprot.org/uniprot/P62993) and https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11187 (http://www.uniprot.org/uniprot/Q07889).

168Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1‐5, http://www.uniprot.org/uniprot/P08833, http://www.uniprot.org/uniprot/P18065, http://www.uniprot.org/uniprot/P17936, http://www.uniprot.org/uniprot/P22692, http://www.uniprot.org/uniprot/P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.

169There 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; https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:5467; http://www.uniprot.org/uniprot/P11717), which lacks classical signalling capacity and appears to subserve a trafficking role [http://www.ncbi.nlm.nih.gov/pubmed/2964083?dopt=AbstractPlus]. INSRR, which has a much more discrete localization, being predominant in the kidney [http://www.ncbi.nlm.nih.gov/pubmed/1530648?dopt=AbstractPlus], 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.

170http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5048 inhibits the insulin‐like growth factor receptor [5], while BMS‐536924 inhibits both the insulin receptor and the insulinlike growth factor receptor [http://www.ncbi.nlm.nih.gov/pubmed/16134929?dopt=AbstractPlus].

171Type 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5323 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:30620, http://www.uniprot.org/uniprot/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.

172Various small molecular inhibitors of type III RTKs have been described, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5687 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5697 (targetting PDGFR, KIT and CSF1R); http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5702 and AC220 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5658; FLT3), as well as pan‐type III RTK inhibitors such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5713 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5711 [http://www.ncbi.nlm.nih.gov/pubmed/15606337?dopt=AbstractPlus]; 5′‐fluoroindirubinoxime has been described as a selective FLT3 inhibitor [2].

173http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00440000236870 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. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5085 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12680, http://www.uniprot.org/uniprot/P15692) is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5086 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12681, http://www.uniprot.org/uniprot/P49765) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5314 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8893, http://www.uniprot.org/uniprot/P49763) activate VEGFR1 homodimers, while VEGFC (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5087, http://www.uniprot.org/uniprot/P49767) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5088 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3708, http://www.uniprot.org/uniprot/O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.

174The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [http://www.ncbi.nlm.nih.gov/pubmed/12443771?dopt=AbstractPlus], Ki8751 [http://www.ncbi.nlm.nih.gov/pubmed/15743179?dopt=AbstractPlus] and ZM323881, a novel inhibitor of vascular endothelial growth factor‐receptor‐2 tyrosine kinase activity [http://www.ncbi.nlm.nih.gov/pubmed/12483548?dopt=AbstractPlus] 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.

175Fibroblast growth factor (FGF) family receptors act as homo‐ and heterodimers, and are characterized by Ig‐like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone‐like FGFs. FGF1‐FGF10 have been identified to act through FGF receptors, while FGF11‐14 appear to signal through intracellular targets. Other family members are less well characterized [http://www.ncbi.nlm.nih.gov/pubmed/21711248?dopt=AbstractPlus].

176Splice variation of the receptors can influence agonist responses. https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3693 (http://www.uniprot.org/uniprot/Q8N441) is a truncated kinase‐null analogue. Various antibodies and tyrosine kinase inhibitors have been developed against FGF receptors [http://www.ncbi.nlm.nih.gov/pubmed/22884522?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20338520?dopt=AbstractPlus]. PD161570 is an FGFR tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/9488112?dopt=AbstractPlus], while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5037 has been described to inhibit FGFR1 and FGFR3 [http://www.ncbi.nlm.nih.gov/pubmed/10987832?dopt=AbstractPlus].

177The 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 [http://www.ncbi.nlm.nih.gov/pubmed/21132015?dopt=AbstractPlus].

178Thus far, no selective PTK7 inhibitors have been described.

179The 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 (http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=334#show_object_1888, also known as nerve growth factor receptor), which has homologies with http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=334, lacks a tyrosine kinase domain, but can signal via ceramide release and nuclear factor θB (NF‐θB) activation. Both trkA and trkB contain two leucine‐rich regions and can exist in monomeric or dimeric forms.

180http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4849 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4846 have been used to label the trkA and trkB receptor, respectively. p75 influences the binding of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5026 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5026, http://www.uniprot.org/uniprot/P01138) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5033 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8023, http://www.uniprot.org/uniprot/P20783) to trkA. The ligand selectivity of p75 appears to be dependent on the cell type; for example, in sympathetic neurones, it binds http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5033 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8023, http://www.uniprot.org/uniprot/P20783) with comparable affinity to trkC [http://www.ncbi.nlm.nih.gov/pubmed/9204912?dopt=AbstractPlus].

181Small molecule agonists of trkB have been described, including LM22A4 [http://www.ncbi.nlm.nih.gov/pubmed/20407211?dopt=AbstractPlus], while ANA12 has been described as a noncompetitive antagonist of BDNF binding to trkB [http://www.ncbi.nlm.nih.gov/pubmed/21505263?dopt=AbstractPlus]. GNF5837 is a family‐selective tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/24900443?dopt=AbstractPlus], while the tyrosine kinase activity of the trkA receptor can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4946 (pIC50= 8.7, [http://www.ncbi.nlm.nih.gov/pubmed/15013000?dopt=AbstractPlus]) and tyrphostin http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4863 [http://www.ncbi.nlm.nih.gov/pubmed/7683492?dopt=AbstractPlus].

182Members 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3548 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:12784, http://www.uniprot.org/uniprot/P41221) binding to a http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=25 thereby forming a cell‐surface multiprotein complex [http://www.ncbi.nlm.nih.gov/pubmed/21078818?dopt=AbstractPlus].

183The muscle‐specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5319 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:329, http://www.uniprot.org/uniprot/O00468) forms a complex with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5320 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6696, http://www.uniprot.org/uniprot/O75096) to activate MuSK [http://www.ncbi.nlm.nih.gov/pubmed/18848351?dopt=AbstractPlus].

184Thus far, no selective MuSK inhibitors have been described.

185HGF receptors regulatematuration 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5315 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11246, http://www.uniprot.org/uniprot/O43278), a serine protease inhibitor. MST1, the ligand of RON, is two disulphide‐linked peptide chains generated by proteolysis of a single gene product.

186PF04217903 is a selective Met tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/22924734?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5057 is an inhibitor of the HGF receptor [http://www.ncbi.nlm.nih.gov/pubmed/14500382?dopt=AbstractPlus], with the possibility of further targets [http://www.ncbi.nlm.nih.gov/pubmed/17595299?dopt=AbstractPlus].

187Members of this RTK family represented a novel structural motif, when sequenced. The ligands for this family, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4935 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:4168, http://www.uniprot.org/uniprot/Q14393) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5050 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:9456, http://www.uniprot.org/uniprot/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.

188AXL tyrosine kinase inhibitors have been described [http://www.ncbi.nlm.nih.gov/pubmed/22247788?dopt=AbstractPlus].

189The TIE family were initially associated with formation of blood vessels. Endogenous ligands are http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4867 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:484, http://www.uniprot.org/uniprot/Q15389), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5316 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:485, http://www.uniprot.org/uniprot/O15123), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4868 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:487, http://www.uniprot.org/uniprot/Q9Y264). http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5316 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:485, http://www.uniprot.org/uniprot/O15123) appears to act as an endogenous antagonist of angiopoietin‐1 function.

190Ephrin 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 (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4908 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3221, http://www.uniprot.org/uniprot/P20827), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4909 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3222, http://www.uniprot.org/uniprot/O43921), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4910 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3223, http://www.uniprot.org/uniprot/P52797), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4911 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3224, http://www.uniprot.org/uniprot/P52798) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4912 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3225, http://www.uniprot.org/uniprot/P52803)) and 1TM proteins for Ephrin B (http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00250000002014: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4913 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3226, http://www.uniprot.org/uniprot/P98172), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4914 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3227, http://www.uniprot.org/uniprot/P52799) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4915 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3228, http://www.uniprot.org/uniprot/Q15768)), although the relationship between ligands and receptors has been incompletely defined.

191Ret proto‐oncogene (Rearranged during transfection) is a transmembrane tyrosine kinase enzyme which is employed as a signalling partner for members of the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=314. 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.

192A number of tyrosine kinase inhibitors targeting RET have been described [http://www.ncbi.nlm.nih.gov/pubmed/21960212?dopt=AbstractPlus].

193The ‘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 [http://www.ncbi.nlm.nih.gov/pubmed/21132015?dopt=AbstractPlus].

194Thus far, no selective RYK inhibitors have been described.

195Discoidin 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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4898 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2197, http://www.uniprot.org/uniprot/P02452), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4899 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2200, http://www.uniprot.org/uniprot/P02458), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4900 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2201, http://www.uniprot.org/uniprot/P02461) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4901 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:2202, http://www.uniprot.org/uniprot/P02462).

196The tyrosine kinase inhibitors of DDR, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5687 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5697, were identified from proteomic analysis [http://www.ncbi.nlm.nih.gov/pubmed/18938156?dopt=AbstractPlus]. Other collagen receptors include glycoprotein VI (http://www.uniprot.org/uniprot/Q9HCN6), leukocyte‐associated immunoglobulin‐like receptor 1 (http://www.uniprot.org/uniprot/Q6GTX8), leukocyte‐associated immunoglobulin‐like receptor 2 (http://www.uniprot.org/uniprot/Q6ISS4) and osteoclast‐associated immunoglobulin‐like receptor (http://www.uniprot.org/uniprot/Q8IYS5).

197http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4903 is a tyrosine kinase inhibitor, anti‐cancer drug targeting ALK and ROS1.

198The 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 [http://www.ncbi.nlm.nih.gov/pubmed/9444961?dopt=AbstractPlus], giving rise to the name AATYK (Apoptosis‐associated tyrosine kinase); while over‐expression induces differentiation in neuroblastoma cells [http://www.ncbi.nlm.nih.gov/pubmed/10837911?dopt=AbstractPlus].

199As yet no selective inhibitors of the LMR family have been described.

200The 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 [http://www.ncbi.nlm.nih.gov/pubmed/23742252?dopt=AbstractPlus].

201Similar 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 [http://www.ncbi.nlm.nih.gov/pubmed/22516751?dopt=AbstractPlus].

202As yet, no selective inhibitors of STYK1 have been described.

203Bergeron JJ et al. (2016) Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction. Annu. Rev. Biochem. 85: 573–97 https://www.ncbi.nlm.nih.gov/pubmed/27023845?dopt=AbstractPlus

204Carvalho 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 https://www.ncbi.nlm.nih.gov/pubmed/26833433?dopt=AbstractPlus

205De Silva DM et al. (2017) Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem. Soc. Trans. 45: 855–870 https://www.ncbi.nlm.nih.gov/pubmed/28673936?dopt=AbstractPlus

206Eklund L et al. (2017) Angiopoietin‐Tie signalling in the cardiovascular and lymphatic systems. Clin. Sci. 131: 87–103 https://www.ncbi.nlm.nih.gov/pubmed/27941161?dopt=AbstractPlus

207Katayama R. (2017) Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)‐rearranged lung cancer. Pharmacol. Ther. 177: 1–8 https://www.ncbi.nlm.nih.gov/pubmed/28185914?dopt=AbstractPlus

208Kazlauskas A. (2017) PDGFs and their receptors. Gene 614: 1–7 https://www.ncbi.nlm.nih.gov/pubmed/28267575?dopt=AbstractPlus

209Ke 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 https://www.ncbi.nlm.nih.gov/pubmed/27717507?dopt=AbstractPlus

210Kuwano M et al. (2016) Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol. Ther. 161: 97–110 https://www.ncbi.nlm.nih.gov/pubmed/27000770?dopt=AbstractPlus

211Lee 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 https://www.ncbi.nlm.nih.gov/pubmed/28167215?dopt=AbstractPlus

212Nelson KN et al. (2017) Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. Trends Mol Med 23: 59–79 https://www.ncbi.nlm.nih.gov/pubmed/27988109?dopt=AbstractPlus

213Simons M et al. (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17: 611–25 https://www.ncbi.nlm.nih.gov/pubmed/27461391?dopt=AbstractPlus

214Stricker S et al. (2017) ROR‐Family Receptor Tyrosine Kinases. Curr. Top. Dev. Biol. 123: 105–142 https://www.ncbi.nlm.nih.gov/pubmed/28236965?dopt=AbstractPlus

215Tan AC et al. (2017) Exploiting receptor tyrosine kinase co‐activation for cancer therapy. Drug Discov. Today 22: 72–84 https://www.ncbi.nlm.nih.gov/pubmed/27452454?dopt=AbstractPlus

216Álvarez‐Aznar A et al. (2017) VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function. Curr. Top. Dev. Biol. 123: 433–482 https://www.ncbi.nlm.nih.gov/pubmed/28236974?dopt=AbstractPlus

217Receptor serine/threonine kinases (RTSK), http://www.genome.jp/kegg‐bin/search_brite?option=‐a&search_string=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 https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3711 (http://www.uniprot.org/uniprot/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 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4933 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:3971, http://www.uniprot.org/uniprot/P19883), which binds and neutralizes activins to prevent activation of the target receptors.

218Endogenous 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 complexmaturation processes [http://www.ncbi.nlm.nih.gov/pubmed/18692464?dopt=AbstractPlus]. 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.

219The 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).

220Batlle E et al. (2019) Transforming Growth Factor‐β Signaling in Immunity and Cancer Immunity 50: 924–940

221Batlle E et al. (2019) Transforming Growth Factor‐β Signaling in Immunity and Cancer Immunity 50: 924‐940

222For the receptors listed below, the exact combination of subunits forming the functional heteromeric receptors is unknown.

223Batlle E et al. (2019) Transforming Growth Factor‐β Signaling in Immunity and Cancer Immunity 50: 924‐940

224A number of endogenous inhibitory ligands have been identified for RSTKs, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4882 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1070, http://www.uniprot.org/uniprot/P12645), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5005 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6065, http://www.uniprot.org/uniprot/P05111), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5008 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:6068, http://www.uniprot.org/uniprot/P55103) and inhibin http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5009 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:24029, http://www.uniprot.org/uniprot/P58166).

225An appraisal of small molecule inhibitors of TGFβ and BMP signalling concluded that TGFβ pathway inhibitors were more selective than BMP signalling inhibitors [http://www.ncbi.nlm.nih.gov/pubmed/21740966?dopt=AbstractPlus]. The authors confirmed the selectivity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6049 to inhibit TGFβ signalling through ALK4, ALK5, ALK7 [http://www.ncbi.nlm.nih.gov/pubmed/14978253?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4907 inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [http://www.ncbi.nlm.nih.gov/pubmed/11602624?dopt=AbstractPlus].

226Smads 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.

227Budi EH et al. (2017) Transforming Growth Factor‐β Receptors and Smads: Regulatory Complexity and Functional Versatility. Trends Cell Biol. 27: 658‐672 [https://www.ncbi.nlm.nih.gov/pubmed/28552280?dopt=AbstractPlus]

228Chen W et al. (2016) Immunoregulation by members of the TGFβ superfamily. Nat. Rev. Immunol. 16: 723‐740 [https://www.ncbi.nlm.nih.gov/pubmed/27885276?dopt=AbstractPlus]

229Heger J et al. (2016) Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure. Br. J. Pharmacol. 173: 3‐14 [https://www.ncbi.nlm.nih.gov/pubmed/26431212?dopt=AbstractPlus]

230Luo JY et al. (2015) Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system. J. Physiol. (Lond.) 593: 2995‐3011 [https://www.ncbi.nlm.nih.gov/pubmed/25952563?dopt=AbstractPlus]

231Macias MJ et al. (2015) Structural determinants of Smad function in TGF‐β signaling. Trends Biochem. Sci. 40: 296‐308 [https://www.ncbi.nlm.nih.gov/pubmed/25935112?dopt=AbstractPlus]

232Morrell NW et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 13: 106‐20 [https://www.ncbi.nlm.nih.gov/pubmed/26461965?dopt=AbstractPlus]

233Neuzillet C et al. (2015) Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 147: 22‐31 [https://www.ncbi.nlm.nih.gov/pubmed/25444759?dopt=AbstractPlus]

234van der Kraan PM. (2017) The changing role of TGFβ in healthy, ageing and osteoarthritic joints. Nat Rev Rheumatol 13: 155‐163 [https://www.ncbi.nlm.nih.gov/pubmed/28148919?dopt=AbstractPlus]

235Receptor 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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:11283) to activate signalling cascades. Family members bind components of the extracellular matrix or cell‐surface proteins indicating a role in intercellular communication.

236Papadimitriou 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 [https://www.ncbi.nlm.nih.gov/pubmed/27693125?dopt=AbstractPlus]

237Stanford SM et al. (2017) Targeting Tyrosine Phosphatases: Time to End the Stigma. Trends Pharmacol. Sci. 38: 524‐540 [https://www.ncbi.nlm.nih.gov/pubmed/28412041?dopt=AbstractPlus]

238Dysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy [http://www.ncbi.nlm.nih.gov/pubmed/23840967?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26008591?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25169849?dopt=AbstractPlus].

239TNFRSF1A 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 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7808 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:7808, http://www.uniprot.org/uniprot/P01138)), brain‐derived neurotrophic factor (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1033 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:1033, http://www.uniprot.org/uniprot/P23560)), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5033 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8023, http://www.uniprot.org/uniprot/P20783) (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8023) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5034 (https://www.genenames.org/data/gene‐symbol‐report/#!/hgnc_id/HGNC:8024, http://www.uniprot.org/uniprot/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 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=304#show_overview_326 of receptor tyrosine kinases. The endogenous ligands for EDAR and EDA2R are, respectively, the membrane (http://www.uniprot.org/uniprot/Q92838#PRO_0000034538) and secreted (http://www.uniprot.org/uniprot/Q92838#PRO_0000034539) isoforms of Ectodysplasin‐A (EDA, http://www.uniprot.org/uniprot/Q92838).

240Blaser H et al. (2016) TNF and ROS Crosstalk in Inflammation. Trends Cell Biol. 26: 249‐261 https://www.ncbi.nlm.nih.gov/pubmed/26791157?dopt=AbstractPlus

241Croft M et al. (2017) Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol 13: 217‐233 https://www.ncbi.nlm.nih.gov/pubmed/28275260?dopt=AbstractPlus

242Kalliolias GD et al. (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12: 49‐62 [PMID:26656660]

243Olesen CM et al. (2016) Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol. Ther. 159: 110‐9 https://www.ncbi.nlm.nih.gov/pubmed/26808166?dopt=AbstractPlus

244von Karstedt S et al. (2017) Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer 17: 352‐366 https://www.ncbi.nlm.nih.gov/pubmed/28536452?dopt=AbstractPlus