The Concise Guide to PHARMACOLOGY 2015/16: Catalytic receptors

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13353/full. G protein‐coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.

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 het-erodimeric functional unit. A fifth group is the receptor tyrosine phosphatases (RTP), which appear to lack cognate ligands, but may be triggered by events such as cell:cell contact and have identified roles in the skeletal, hematopoietic and immune systems. A sixth group of catalytic receptors in the Guide is the integrins, which have roles in cell:cell communication, often associated with signaling in the blood.  6018 Tumour necrosis factor (TNF) receptor family membrane 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 func-tion principally as transcription factors in the nucleus.
Type I cytokine receptors are characterized by two pairs of conserved cysteines linked via disulfide bonds and a C-terminal WSXWS motif within their CHD. Type I receptors are commonly classified into five groups, based on sequence and structual homology of the receptor and its cytokine ligand, which is potentially more reflective of evolutionary relationships than an earlier scheme based on the use of common signal transducing chains within a receptor complex. These are the IL-2, IL-3, IL-6, IL-12 and prolactin families.
Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif. The type II cytokine receptors include the interferon, IL-10, IL-1 and IL-17 receptors.

Catalytic receptors
Cytokine receptor family IL-2 receptor family Overview: The IL-2 receptor family consists of one or more ligand-selective subunits, and a common γ chain (γc): IL2RG, P31785), though IL-4 and IL-7 receptors can form complexes with other receptor chains. Receptors of this family associate with Jak1 and Jak3, primarily activating Stat5, although certain family members can also activate Stat1, Stat3, or Stat6. Ro264550 has been described as a selective IL-2 receptor antagonist, which binds to IL-2 [177].

Catalytic receptors
Cytokine receptor family IL-3 receptor family Overview: The IL-3 receptor family signal through a receptor complex comprising of a ligand-specific α subunit and a common β chain (CSF2RB, P32927), which is associated with Jak2 and signals primarily through Stat5.

Comments:
Inhibitors of other receptor tyrosine kinases, such as semaxanib, which inhibits VEGF receptor function, may also inhibit Ret function [131]. Mutations of RET and GDNF genes may be involved in Hirschsprung's disease, which is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.

Further Reading
Allen SJ et al.

Catalytic receptors Integrins
Overview: Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.
Integrins are heterodimeric entities, composed of α and β subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its α subunit, and if present (in α1, α2, α10, α11, αD, αE, αL, αM and αX), this I domain contains the ligand binding site. All β subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an α subunit I domain precludes ligand binding through the β subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg 2+ ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity via inside-out signalling and ligand binding to integrins can regulate cellular activity via outside-in signalling.

Comments: Integrin ligands
Collagen is the most abundant protein in metazoa, rich in glycine and proline residues, made up of cross-linked triple helical structures, generated primarily by fibroblasts. Extensive posttranslational processing is conducted by prolyl and lysyl hydrox-ylases, as well as transglutaminases. Over 40 genes for collagenα subunits have been identified in the human genome. The collagen-binding integrins α1β1, α2β1, α10β1 and α11β1 recognise a range of triple-helical peptide motifs including GFOGER (O = hydroxyproline), a synthetic peptide derived from the primary sequence of collagen I (COL1A1 (COL1A1, P02452)) and collagen II (COL2A1 (COL2A1, P02458)).
Laminin is an extracellular glycoprotein composed of α, β and γ chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to α1β1, α2β1, α3,β1, is a glycosylated hexamer composed of two α (FGA, P02671), two β (FGB, P02675) and two γ (FGG, P02679,) subunits, linked by disulphide bridges. It is found in plasma and alpha granules of platelets. It forms cross-links between activated platelets mediating aggregation by binding αIIbβ3; proteolysis by thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation cascade.
fibronectin (FN1, P02751) is a disulphide-linked homodimer found as two major forms; a soluble dimeric form found in the plasma and a tissue version that is polymeric, which is secreted into the extracellular matrix by fibroblasts. Splice variation of the gene product (FN1, P02751) generates multiple isoforms. vitronectin (VTN, P04004) is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide -linked dimer. osteopontin (SPP1, P10451) forms an integral part of the mineralized matrix in bone, where it undergoes extensive posttranslation processing, including proteolysis and phosphorylation. von Willebrand factor (VWF, P04275) is a glycoprotein synthesised in vascular endothelial cells as a disulphide-linked homodimer, but multimerises further in plasma and is deposited on vessel wall collagen as a high molecular weight multimer. It is responsible for capturing platelets under arterial shear flow (via GPIb) and in thrombus propagation (via integrin αIIbβ3).

Natriuretic peptide receptor family
Catalytic receptors Natriuretic peptide receptor family Overview: Natriuretic peptide receptors (provisional nomenclature) are a family of homodimeric, catalytic receptors with a single TM domain and guanylyl cyclase (EC 4.6.1.2) activity on the intracellular domain of the protein sequence. Isoforms are activated by the peptide hormones atrial natriuretic peptide (NPPA, P01160), brain natriuretic peptide (NPPB, P16860) and C-type natriuretic peptide (NPPC, P23582). Another family member is GC-C, the receptor for guanylin (GUCA2A, Q02747) and uroguanylin (GUCA2B, Q16661) . Family members have conserved ligand-binding, catalytic (guanylyl cyclase) and regulatory domains with the exception of NPR-C which has an extracellular binding domain homologous to that of other NPRs, but with a truncated intracellular domain which appears to couple, via the G i/o family of G-proteins, to activation of phospholipase C, inwardly-rectifying potassium channels and inhibition of adenylyl cyclase activity [136]. Comments: The polysaccharide obtained from fermentation of Aureobasidium species, HS142-1, acts as an antagonist at both NPR-A and NPR-B receptors [132].

Catalytic receptors Pattern recognition receptors
Overview: Pattern Recognition Receptors (PRRs, [174]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [18]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs include both cellsurface and intracellular proteins, including toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs, also known as NOD-like receptors) and the mannose receptor family (ENSFM00250000004089). PRRs may be divided into signalling-associated members, identified here, and endocytic members (such as the mannose receptor family), the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction.
PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogenassociated molecular patterns, which includes peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids.

Catalytic receptors Pattern recognition receptors Toll-like receptor family
Overview: Members of the toll-like family of receptors (nomenclature recommended by the NC-IUPHAR subcommittee on pattern recognition receptors, [18]) share significant homology with the interleukin-1 receptor family and appear to require dimerization either as homo-or heterodimers for functional activity.
Functions as a heterodimer with either TLR1 or TLR6 in the detection of triacylated and diacylated lipopeptides respectively. TLR1/2 and 2/6 heterodimers can be activated by the synthetic lipopeptides Pam3CSK4 and Pam2CSK4 respectively. There is some debate in the field as to whether or not peptidoglycan is a direct agonist of TLR2, or whether the early studies reporting this contained contaminating lipoproteins.
Involved in endosomal detection of dsRNA; pro-inflammatory. eritoran (E5564) is a lipid A analogue, which has been described as a TLR4 antagonist [80]. TLR4 signals in conjunction with the co-factor MD2.
Loss-of-function mutations of NLRP3 are associated with cold autoinflammatory and Muckle-Wells syndromes. This family also includes NLR family, apoptosis inhibitory protein (NAIP, Q13075) which can be found in the 'Inhibitors of apop-tosis (IAP) protein family' in the Other protein targets section of the Guide.

Overview:
Receptor serine/threonine kinases (RTSK), EC 2.7.11.30, respond to particular cytokines, the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) families, and may be divided into two subfamilies on the basis of structural similarities. Agonist binding initiates formation of a cell-surface complex of type I and type II RSTK, possibly heterotetrameric, where where both subunits express serine/threonine kinase activity. The type I receptor serine/threonine kinases are also known as activin receptors or activin receptor-like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1-7). The type II protein phosphorylates the kinase domain of the type I partner (sometimes referred to as the signal propagating subunit), causing displacement of the protein partners, such as the FKBP12 FK506-binding protein FKBP1A (P62942) and allowing the binding and phosphorylation of particular members of the Smad family. These migrate to the nucleus and act as complexes to regulate gene transcription. Type III receptors, sometimes called co-receptors or accessory proteins, regulate the signalling of the receptor complex, in either enhancing (for example, presenting the ligand to the receptor) or inhibitory manners. TGFβ family ligand signalling may be inhibited by endogenous proteins, such as follistatin (FST, P19883), which binds and neutralizes activins to prevent activation of the target receptors. Endogenous agonists, approximately 30 in man, are often described as paracrine messengers acting close to the source of production.
They are characterized by six conserved cysteine residues and are divided into two subfamilies on the basis of sequence comparison and signalling pathways activated, the TGFβ/activin/nodal subfamily and the BMP/GDF (growth/differentiation factor)/MIS (Müllerian inhibiting substance) subfamily. Ligands active at RSTKs appear to be generated as large precursors which undergo complex maturation processes [105]. Some are known to form disulphide-linked homo-and/or heterodimeric complexes. Thus, inhibins are α subunits linked to a variety of β chains, while activins are combinations of β subunits. ). An appraisal of small molecule inhibitors of TGFβ and BMP signalling concluded that TGFβ pathway inhibitors were more selective than BMP signalling inhibitors [186]. The authors confirmed the selectivity of TGF-beta RI inhibitor III to inhibit TGFβ signalling through ALK4, ALK5, ALK7 [36]. Dorsomorphin inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [209]. Smads were identified as mammalian orthologues of Drosophila genes termed "mothers against decapentaplegic" and may be divided into Receptor-regulated Smads (R-Smads, including Smad1, Smad2, Smad3, Smad5 and Smad8), Co-mediated Smad (Co-Smad, Smad4) and Inhibitory Smads (I-Smad, Smad6 and Smad7). R-Smads form heteromeric complexes with Co-Smad. I-Smads compete for binding of R-Smad with both receptors and Co-Smad.

Catalytic receptors Receptor kinases TK: Tyrosine kinase Receptor tyrosine kinases
Overview: Receptor 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 [14,62,184]. In the human genome, 58 RTKs have been identified, which fall into 20 families [102]. All RTKs display an extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity (occasionally split into two domains by an insertion, termed the kinase insertion), with juxta-membrane and C-terminal regulatory regions. Agonist binding to the extracellular domain evokes dimerization, and sometimes oligomerization, of RTKs (a small subset of RTKs forms multimers even in the absence of activating ligand). This leads to autophosphorylation in the tyrosine kinase domain in a trans orientation, serving as a site of assembly of protein complexes and stimulation of multiple signal transduction pathways, including phospholipase C-γ, mitogen-activated protein kinases and phosphatidylinositol 3-kinase [184]. RTKs are of widespread interest not only through physiological functions, but also as drug targets in many types of cancer and other disease states. Many diseases result from genetic changes or abnormalities that either alter the activity, abundance, cellular distribution and/or regulation of RTKs. Therefore, drugs that modify the dysregulated functions of these RTKs have been developed which fall into two categories. One group is often described as 'biologicals', which block the activation of RTKs directly or by chelating the cognate ligands, while the second are small molecules designed to inhibit the tyrosine kinase activity directly.

Type I RTKs: ErbB (epidermal growth factor) receptor family
Catalytic receptors Receptor kinases TK: Tyrosine kinase Receptor tyrosine kinases Type I RTKs: ErbB (epidermal growth factor) receptor family Overview: ErbB family receptors are Class I receptor tyrosine kinases [62]. ERBB2 (also known as HER-2 or NEU) appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand [63]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell-surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed in many cancers, particularly forms of breast cancer.
Nomenclature epidermal growth factor receptor erb-b2 receptor tyrosine kinase 2 erb-b2 receptor tyrosine kinase 3 erb-b2 receptor tyrosine kinase 4  [62], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post-translationally into two peptides, which then cross-link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post-translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889). Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1-5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.

Nomenclature
Insulin receptor Insulin-like growth factor I receptor Insulin receptor-related receptor insulin-like growth factor 1 (IGF1, P05019), insulin-like growth factor 2 (IGF2, P01344) -Comments: There is evidence for low potency binding and activation of insulin receptors by IGF1. IGF2 also binds and activates the cation-independent mannose 6-phosphate receptor (also known as the insulin-like growth factor II receptor), which lacks classical signalling capacity and appears to subserve a traf-ficking role [115]. INSRR, which has a much more discrete localization, being predominant in the kidney [95], currently lacks a cognate ligand or evidence for functional impact. Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.

Comments:
The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [49], Ki8751 [94] and ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity [195] are described as VEGFR2-selective tyrosine kinase inhibitors. Bevacizumab is a monoclonal antibody directed against VEGF-A, used clinically for the treatment of certain metastatic cancers; an antibody fragment has been used for wet age-related macular degeneration.

Catalytic receptors
Receptor kinases TK: Tyrosine kinase Receptor tyrosine kinases Type V RTKs: FGF (fibroblast growth factor) receptor family Overview: Fibroblast growth factor (FGF) family receptors act as homo-and heterodimers, and are characterized by Ig-like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been im-plicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone-like FGFs. FGF1-FGF10 have been identified to act through FGF receptors, while FGF11-14 appear to signal through intracellular targets. Other family members are less well characterized [194].

Comments:
Splice variation of the receptors can influence agonist responses. FGFRL1 (Q8N441) is a truncated kinase-null analogue. Various antibodies and tyrosine kinase inhibitors have been developed against FGF receptors [107,210]. PD161570 is an FGFR tyrosine kinase inhibitor [10], while PD173074 has been described to inhibit FGFR1 and FGFR3 [169].

Type VI RTKs: PTK7/CCK4
Catalytic receptors Receptor kinases TK: Tyrosine kinase Receptor tyrosine kinases Type VI RTKs: PTK7/CCK4 Overview: The PTK7 receptor is associated with polarization of epithelial cells and the development of neural structures. Sequence analysis suggests that the gene product is catalytically inactive as a protein kinase, although there is evidence for a role in Wnt signalling [152]. with comparable affinity to trkC [40]. Small molecule agonists of trkB have been described, including LM22A4 [123], while ANA12 has been described as a noncompetitive antagonist of BDNF binding to trkB [23]. GNF5837 is a family-selective tyrosine kinase inhibitor [4], while the tyrosine kinase activity of the trkA receptor can be inhibited by GW441756 (p IC 50= 8.7, [200]) and tyrphostin AG879 [142]. Overview: HGF receptors regulate maturation of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post-translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by HGF-inhibitor 1 (SPINT1, O43278), a serine protease inhibitor. MST1, the ligand of RON, is two disulphide-linked peptide chains generated by proteolysis of a single gene product.  [34].SU11274 is an inhibitor of the HGF receptor [162], with the possibility of further targets [8].  Endogenous ligands growth arrest specific protein 6 (GAS6, Q14393) [138], protein S (PROS1, P07225) [172] growth arrest specific protein 6 (GAS6, Q14393) [138], protein S (PROS1, P07225) [172] growth arrest specific protein 6 (GAS6, Q14393) [138] Comments: AXL tyrosine kinase inhibitors have been described [130]. Overview: Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are structurally-related membrane protein tyrosine kinases activated by collagen. Collagen is probably the most abundant protein in man, with at least 29 families of genes encoding proteins, which undergo splice variation and post-translational processing, and may exist in monomeric or polymeric forms, producing a triple-stranded, twine-like structure. In man, principal family members include COL1A1 (COL1A1, P02452), COL2A1 (COL2A1, P02458), COL3A1 (COL3A1, P02461) and COL4A1 (COL4A1, P02462).

Comments:
The tyrosine kinase inhibitors of DDR, imatinib and nilotinib, were identified from proteomic analysis [39]. Other collagen receptors include glycoprotein VI (Q9HCN6), leukocyte-associated immunoglobulin-like receptor 1 (Q6GTX8), leukocyte-associated immunoglobulin-like receptor 2 (Q6ISS4) and osteoclast-associated immunoglobulin-like receptor (Q8IYS5). Overview: The LMR kinases are unusual amongst the RTKs in possessing a short extracellular domain and extended intracellular domain (hence the 'Lemur' name reflecting the long tail). A precise function for these receptors has yet to be defined, although LMR1 was identified as a potential marker of apoptosis [52], giving rise to the name AATYK (Apoptosis-associated tyrosine kinase); while over-expression induces differentiation in neuroblastoma cells [156].
Nomenclature apoptosis-associated tyrosine kinase lemur tyrosine kinase 2 lemur tyrosine kinase 3 Overview: The LTK family appear to lack endogenous ligands. LTK is subject to tissue-specific splice variation, which appears to generate products in distinct subcellular locations. ALK fusions created by gene translocations and rearrangements are associated with many types of cancer, including large cell lymphomas, inflammatory myofibrilastic tumours and non-small cell lung cancer [120].
Nomenclature leukocyte receptor tyrosine kinase anaplastic lymphoma receptor tyrosine kinase Comments -crizotinib appears to be a selective ALK inhibitor acting on the tyrosine kinase activity [58] Type XX RTKs: STYK1 Catalytic receptors Receptor kinases TK: Tyrosine kinase Receptor tyrosine kinases Type XX RTKs: STYK1 Overview: Similar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. STYK1 (also known as Novel Oncogene with Kinase-domain, NOK) has been suggested to co-localize with activated EGF receptor [43].

Catalytic receptors
Tumour necrosis factor (TNF) receptor family Overview: The TNF receptor superfamily (TNFRSF, provisional nomenclature) displays limited homology beyond an extracellular domain rich in cysteine residues and is activated by at least 18 different human homologues of TNF referred to as the TNF superfamily (TNFSF). Some homologues lacking transmembrane and cytoplasmic domains function as decoy receptors binding ligand without inducing cell signalling. Many of these receptors and ligands function as multimeric entities. Sig-nalling 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 B or mitogen-activated protein kinase pathways. Pharmacolog-ical 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.  Adaptor proteins  TRADD  TRAF1, TRAF2, TRAF5  TRAF3, TRAF4, TRAF5  TRAF1, TRAF2, TRAF3,  TRAF5   TRAF1, TRAF2,  TRAF3, TRAF5  Endogenous ligands --ectodysplasin A2 (EDA, Q92838) [204] ectodysplasin A1 (EDA, Q92838) [204] Comments: TNFRSF1A is preferentially activated by the shed form of TNF ligand, whereas the membrane-bound form of TNF serves to activate TNFRSF1A and TNFRSF1B equally. The neurotrophins nerve growth factor (NGF (NGF, P01138)), brain-derived neurotrophic factor (BDNF (BDNF, P23560)), neurotrophin-3 (NTF3, P20783) (NTF3) and neurotrophin-4 (NTF4, P34130) (NTF4) are structurally unrelated to the TNF ligand superfamily but exert some of their actions through the "low affinity nerve growth factor receptor" (NGFR (TNFRSF16)) as well as through the TRK family of receptor tyrosine kinases.