THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Catalytic receptors

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15541. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Overview: Catalytic receptors are cell-surface proteins, usually dimeric in nature, which encompass ligand binding and functional domains in one polypeptide chain. The ligand binding domain is placed on the extracellular surface of the plasma membrane and separated from the functional domain by a single transmembrane-spanning domain of 20-25 hydrophobic amino acids. The functional domain on the intracellular face of the plasma membrane has catalytic activity, or interacts with particular enzymes, giving the superfamily of receptors its name. Endogenous agonists of the catalytic receptor superfamily are peptides or proteins, the binding of which may induce dimerization of the receptor, which is the functional version of the receptor.
Amongst the catalytic receptors, particular subfamilies may be readily identified dependent on the function of the enzymatic portion of the receptor. The smallest group is the particulate guanylyl cyclases of the natriuretic peptide receptor family. The most widely recognized group is probably the receptor tyrosine kinase (RTK) family, epitomized by the neurotrophin receptor family, where a crucial initial step is the activation of a signalling cascade by autophosphorylation of the receptor on intracellular tyrosine residue(s) catalyzed by enzyme activity intrinsic to the receptor. A third group is the extrinsic protein tyrosine kinase receptors, where the catalytic activity resides in a separate protein from the binding site. Examples of this group include the GDNF and ErbB receptor families, where one, catalytically silent, member of the heterodimer is activated upon binding the ligand, causing the second member of the heterodimer, lacking ligand binding capacity, to initiate signaling through tyrosine phosphorylation. A fourth group, the receptor threonine/serine kinase (RTSK) family, exemplified by TGF-β and BMP receptors, has intrinsic serine/threonine protein kinase activity in the heterodimeric functional unit. A fifth group is the receptor tyrosine phosphatases (RTP), which appear to lack cognate ligands, but may be triggered by events such as cell:cell contact and have identified roles in the skeletal, hematopoietic and immune systems.
A further group of catalytic receptors for the Guide is the integrins, which have roles in cell:cell communication, often associated with signaling in the blood.

S265
Cytokine Receptor tyrosine phosphatase (RTP) family S308 Tumour necrosis factor (TNF) receptor family type III (FBNIII)-like domains, a transmembrane domain, and intracellular homology domains. An unusual feature of this group of agents is the existence of soluble and decoy receptors. These bind cytokines without allowing signalling to occur. A further attribute is the production of endogenous antagonist molecules, which bind to the receptors selectively and prevent signalling. A commonality of these families of receptors is the ligand-induced homo-or hetero-oligomerisation, which results in the recruitment of intracellular protein partners to evoke cellular responses, particularly in inflammatory or haematopoietic signalling. Although not an exclusive signalling pathway, a common feature of the majority of cytokine receptors is activation of the JAK/STAT pathway. This cascade is based around the protein tyrosine kinase activity of the Janus kinases (JAK), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo-or heterodimeric STATs function principally as transcription factors in the nucleus.
Type I cytokine receptors are characterized by two pairs of conserved cysteines linked via disulfide bonds and a C-terminal WSXWS motif within their CHD. Type I receptors are commonly classified into five groups, based on sequence and structual homology of the receptor and its cytokine ligand, which is potentially more reflective of evolutionary relationships than an earlier scheme based on the use of common signal transducing chains within a receptor complex.
Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif. Comments Decoy receptor that binds IL-13 (IL13, P35225) as a monomer. ---

IL-3 receptor family
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 [165]. 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.

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 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.
Laminin is an extracellular glycoprotein composed of α, β and γ chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to α1β1, α2β1, α3,β1, α7β1 and α6β4 integrins10. fibronectin (FN1, P02751) is a disulphide-linked homodimer found as two major forms; a soluble dimeric form found in the plasma and a tissue version that is polymeric, which is secreted into the extracellular matrix by fibroblasts. Splice variation of the gene product (FN1, P02751) generates multiple isoforms.
vitronectin (VTN, P04004) is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide -linked dimer.
osteopontin (SPP1, P10451) forms an integral part of the mineralized matrix in bone, where it undergoes extensive post-translation processing, including proteolysis and phosphorylation.
von Willebrand factor (VWF, P04275) is a glycoprotein synthesised in vascular endothelial cells as a disulphide-linked homodimer, but multimerises further in plasma and is deposited on vessel wall collagen as a high molecular weight multimer. It is responsible for capturing platelets under arterial shear flow (via GPIb) and in thrombus propagation (via integrin αIIbβ3).  [218]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [24]) 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.

Toll-like receptor family
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, [24]) 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, [219,220] 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 [106]. TLR4 signals in conjunction with the co-factor MD-2 (LY96).
Involved in the detection of bacterial flagellin; pro-inflammatory.
TLR10 is the only pattern-recognition receptor without known ligand specificity and biological function. Evidence suggests it plays a modulatory role with predominantly inhibitory (anti-inflammatory) actions [182]. Murine TLR10 has a retroviral insertion that makes it non-functional.

NOD-like receptor family
Catalytic receptors → Pattern recognition receptors → NOD-like receptor family Overview: The nucleotide-binding oligomerization domain, leucine-rich repeat (NLR) family of receptors (nomenclature recommended by the NC-IUPHAR subcommittee on pattern recognition receptors [24]) share a common domain organisation. This consists of an N-terminal effector domain, a central nucleotide-binding and oligomerization domain (NOD; also referred to as a NACHT domain), and C-terminal leucine-rich repeats (LRR) which have regulatory and ligand recognition functions. The type of effector domain has resulted in the division of NLR family members into two major sub-families, NLRC and NLRP, along with three smaller sub-families NLRA, NLRB and NLRX [222]. NLRC members express an N-terminal caspase recruitment domain (CARD) and NLRP members an N-terminal Pyrin domain (PYD).
Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase RIPK2 (receptor interacting serine/threonine kinase 2, O43353, also known as CARD3, CARDIAK, RICK, RIP2) leading to signalling through NFκB and MAP kinase. Activation of NLRC4 (previously known as IPAF) and members of the NLRP3 family, including NLRP1 and NLRP3, leads to formation of a large multiprotein complex known as the inflammasome. In addition to NLR proteins other key members of the inflammasome include the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD, also known as PYCARD, CARD5, TMS1, Q9ULZ3) and inflammatory caspases. The inflammasome activates the pro-inflammatory cytokines IL-1β (IL1B, P01584) and IL-18 (IL18, Q14116) [24,43].  Along with NLRP7, NLRP2 is the product of a primate-specific gene duplication.
NLRP3 has been shown to be activated following disruption of cellular haemostasis by a wide-variety of exogenous and endogenous molecules. The identity of the precise agonist that interacts with NLRP3 remains enigmatic. Efflux of potassium ions appears to be a common event for NLRP3 activating molecules. In addition to MCC950 [36] other small molecules including CY-09 [109], β-hydroxybutyrate [257], and various boron containing compounds [9] modulate NLRP3.
Expanded in the mouse resulting in 7 orthologues.
--Absent in mouse. Along with NLRP2 the product of a primate-specific gene duplication.
Comments Absent in mouse This receptor has three murine orthologues.
NLRP10 lacks the LRR region.
Loss-of-function mutations of NLRP3 are associated with cold autoinflammatory and Muckle-Wells syndromes.
This family also includes NLR family, apoptosis inhibitory protein (NAIP, Q13075) which can be found in the 'Inhibitors of apoptosis (IAP) protein family' in the Other protein targets section of the Guide.

RIG-I-like receptor family
Catalytic receptors → Pattern recognition receptors → RIG-I-like receptor family Overview: There 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 [23,24]. They function as RNA helicases (EC 3.6.4.13) using the energy from ATP hydrolysis to unwind RNA.   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 [169].

Receptor tyrosine kinases (RTKs)
Catalytic receptors → Receptor kinases → TK: Tyrosine kinase → Receptor tyrosine kinases (RTKs) Overview: Receptor tyrosine kinases (RTKs), a family of cell-surface receptors, which transduce signals to polypeptide and protein hormones, cytokines and growth factors are key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, cell migration and cell cycle control [16,77,230]. In the human genome, 58 RTKs have been identified, which fall into 20 families [132].
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 [230].
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.   [77]. 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 [78]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell-surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed in many cancers, particularly forms of breast cancer and lung cancer. Mutations in the EGFR are responsible for acquired resistance to tyrosine kinase inhibitor chemotherapeutics.  [77], 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

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

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 2 receptor; IGF2R; P11717), which lacks classical signalling capacity and appears to subserve a trafficking role [146]. INSRR, which has a much more discrete localization, being predominant in the kidney [124], currently lacks a cognate ligand or evidence for functional impact.
Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.
PQ401 inhibits the insulin-like growth factor receptor [5], while BMS-536924 inhibits both the insulin receptor and the insulin-like growth factor receptor [245]. Comments Upregulation of CSF1R expression is associated with migroglial activation and immune pathology in Alzhermer's disease (AD) [74,75]. Pharmacological inhibition of CSF1R with GW-2580 reduces microglial proliferation and prevents disease progression in a mouse model of AD, but this does not correlate with amyloid-β plaque numbers [180].
Comments: Various small molecular inhibitors of type III RTKs have been described, including imatinib and nilotinib (targetting PDGFR, KIT and CSF1R); midostaurin and AC220 (quizartinib; FLT3), as well as pan-type III RTK inhibitors such as sunitinib and sorafenib [186]; 5'-fluoroindirubinoxime has been described as a selective FLT3 inhibitor [2]. Overview: Fibroblast growth factor (FGF) family receptors act as homo-and heterodimers, and are characterized by Ig-like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone-like FGFs. FGF1-FGF10 have been identified to act through FGF receptors, while FGF11-14 appear to signal through intracellular targets. Other family members are less well characterized [241].

Nomenclature
fibroblast growth factor receptor 1 fibroblast growth factor receptor 2 fibroblast growth factor receptor 3 fibroblast growth factor receptor 4  Agonists -palifermin --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 [136,264]. PD161570 is an FGFR tyrosine kinase inhibitor [11], while PD173074 has been described to inhibit FGFR1 and FGFR3 [209]. 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 [190].

Nomenclature
protein tyrosine kinase 7 (inactive) The neurotrophin receptor family of RTKs include trkA, trkB and trkC (tropomyosin-related kinase) receptors, which respond to NGF, BDNF and neurotrophin-3, respectively. They are associated primarily with proliferative and migration effects in neural systems. Various isoforms of neurotrophin receptors exist, including truncated forms of trkB and trkC, which lack catalytic domains. p75 (TNFRSF16, also known as nerve growth factor receptor), which has homologies with tumour necrosis factor receptors, lacks a tyrosine kinase domain, but can signal via ceramide release and nuclear factor κB (NF-κB) activation. Both trkA and trkB contain two leucine-rich regions and can exist in monomeric or dimeric forms. influences the binding of NGF (NGF, P01138) and neurotrophin-3 (NTF3, P20783) to trkA. The ligand selectivity of p75 appears to be dependent on the cell type; for example, in sympathetic neurones, it binds neurotrophin-3 (NTF3, P20783) with comparable affinity to trkC [46].

Type VIII RTKs: ROR family
Catalytic receptors → Receptor kinases → TK: Tyrosine kinase → Receptor tyrosine kinases (RTKs) → Type VIII RTKs: ROR family Overview: Members of the ROR family appear to be activated by ligands complexing with other cell-surface proteins. Thus, ROR1 and ROR2 appear to be activated by Wnt-5a (WNT5A, P41221) binding to a Frizzled receptor thereby forming a cell-surface multiprotein complex [80].
Nomenclature receptor tyrosine kinase like orphan receptor 1 receptor tyrosine kinase like orphan receptor 2 Overview: The muscle-specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. Agrin (AGRN, O00468) forms a complex with low-density lipoprotein receptor-related protein 4 (LRP4, O75096) to activate MuSK [117].
Nomenclature muscle associated receptor tyrosine kinase

Type X RTKs: HGF (hepatocyte growth factor) receptor family
Catalytic receptors → Receptor kinases → TK: Tyrosine kinase → Receptor tyrosine kinases (RTKs) → Type X RTKs: HGF (hepatocyte growth factor) receptor family Overview: HGF receptors regulate maturation of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post-translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by HGF-inhibitor 1 (SPINT1, O43278), a serine protease inhibitor. MST1, the ligand of RON, is two disulphide-linked peptide chains generated by proteolysis of a single gene product.

) [25] -
Comments: PF04217903 is a selective Met tyrosine kinase inhibitor [40]. SU11274 is an inhibitor of the HGF receptor [198], with the possibility of further targets [6]. Overview: Members of this RTK family represented a novel structural motif, when sequenced. The ligands for this family, growth arrest specific protein 6 (GAS6, Q14393) and protein S (PROS1, P07225), are secreted plasma proteins which undergo vitamin K-dependent post-translational modifications generating carboxyglutamate-rich domains which are able to bind to negatively-charged surfaces of apoptotic cells.

Nomenclature
ret proto-oncogene Comments: A number of tyrosine kinase inhibitors targeting RET have been described [56].

Overview:
The 'related to tyrosine kinase receptor' (Ryk) is structurally atypical of the family of RTKs, particularly in the activation and ATP-binding domains. RYK has been suggested to lack kinase activity and appears to be involved, with FZD8, in the Wnt signalling system [190]. 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 [45]. 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 [66], giving rise to the name AATYK (Apoptosis-associated tyrosine kinase); while over-expression induces differentiation in neuroblastoma cells [192].

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 [152]. Comments -Crizotinib appears to be a selective ALK inhibitor acting on the tyrosine kinase activity [71]  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 [50].

Nomenclature
serine/threonine/tyrosine kinase 1 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 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 [135]. 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.

Nomenclature
HGNC gene symbol Uniprot ID Other names Receptor tyrosine phosphatase (RTP) family

Catalytic receptors → Receptor tyrosine phosphatase (RTP) family
Overview: Receptor tyrosine phosphatases (RTP) are cell-surface proteins with a single TM region and intracellular phosphotyrosine phosphatase activity. Many family members exhibit constitutive activity in heterologous expression, dephosphorylating intracellular targets such as Src tyrosine kinase (SRC) to activate signalling cascades. Family members bind components of the extracellular matrix or cell-surface proteins indicating a role in intercellular communication.
Only identified in mouse to date. A potential decoy receptor for the cytotoxic ligand TNFSF10/TRAIL. Does not contain a cytoplasmic death domain so does not induce apoptosis, and does not activate the NF-κB signalling pathway.
Receptor for the EDA-A2 isoform of ectodysplasin encoded by the anhidrotic ectodermal dysplasia (EDA) gene.
Cell surface receptor for ectodysplasin A (a morphogen involved in the development of ectodermal tissues, including skin, hair, nails, teeth, and sweat glands).