Scholarly article on topic 'The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors'

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Academic research paper on topic "The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors"

THE CONCISE GUIDE TO PHARMACOLOGY 2013/14: CATALYTIC RECEPTORS

Stephen P.H. Alexander*1, Helen E. Benson2, Elena Faccenda2, Adam J. Pawson2, Joanna L. Sharman2, Michael Spedding3, John A. Peters4, Anthony J. Harmar2 and CGTP Collaborators

*Author for correspondence;steve.alexander@guidetopharmacology.org 1 School of Life Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK 2The University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK 3Spedding Research Solutions SARL, Le Vesinet 78110, France

4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 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.12444/full.

Catalytic receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.

It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. 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 the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

BRITISH

PHARMACOLOGICAL

SOCIETY

DDI 9SY, UK

International Union of Basic and Clinical Pharmacology

An Introduction to Catalytic Receptors

Catalytic receptors are cell-surface proteins, usually dimeric in nature, which typically 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 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-|3 and BMP receptors, has intrinsic serine/threonine protein kinase activity in the heterodimeric functional unit. A fifth group is the receptor tyrosine phos-phatases (RTP), which generally 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 new group of catalytic receptors for the Guide is the integrins, which have roles in cell : cell communication, often associated with signalling in the blood.

Acknowledgements

We wish to acknowledge the tremendous help provided by the Consultants to the Guides past and present (see list in the Overview, p. 1452). We are extremely grateful for the financial contributions from the British Pharmacological Society, the International Union of Basic and Clinical Pharmacology, the Wellcome Trust (099156/Z/12/Z]), which support the website and the University of Edinburgh, who host the guidetopharmacology.org website.

Conflict of interest

The authors state that there is no conflict of interest to disclose.

List of records presented

1678 Cytokine receptor family

1684 GDNF receptor family

1685 Integrins

1688 Natriuretic peptide receptor family

1689 Pattern Recognition receptors

1692 Receptor serine/threonine kinase (RSTK) family

1695 Receptor tyrosine kinases

1702 Receptor tyrosine phosphatases (RTP)

1703 Tumour necrosis factor (TNF) receptor family

Cytokine receptor family

Overview: Cytokines are not a clearly defined group of agents, other than having an impact on immune signalling pathways, although many cytokines have effects on other systems, such as in development. A feature of some cytokines, which allows them to be distinguished from hormones, is that they may be produced by "non-secretory" cells, for example, endothelial cells. Within the cytokine receptor family, some subfamilies may be identified, which are described elsewhere in the Guide to PHARMACOLOGY, receptors for the TNF family, the TGF-P family and the chemokines. Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. These receptors possess a conserved extracellular region, known as the cytokine receptor homology domain (CHD), along with a range of other structural modules, including extracellular immuno-

globulin (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 heterodi-meric 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.

IL-2 receptor family

Overview: The IL-2 receptor family consists of one or more ligand-selective subunits, and a common y chain (-yc): 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 [3].

Nomenclature Interleukin-2 receptor Interleukin-4 receptor type I Interleukin-4 receptor type II Interleukin-7 receptor Interleukin-9 receptor

Subunits Interleukin-2 receptor a subunit (Ligand-binding subunit), Interleukin-2 receptor p subunit (Ligand-binding subunit), Interleukin-2 receptor y subunit (Other subunit) Interleukin 4 receptor (Ligand-binding subunit), Interleukin-2 receptor y subunit (Other subunit) Interleukin 4 receptor (Ligand-binding subunit), Interleukin 13 receptor, al (Other subunit) Interleukin 7 receptor (Ligand-binding subunit), Interleukin-2 receptor y subunit (Other subunit) Interleukin 9 receptor (Ligand-binding subunit), Interleukin-2 receptor y subunit (Other subunit)

Endogenous agonists IL-2 (IL2, P60568) IL-4 (IL4, P05112) IL-13 (IL13, P35225), IL-4 (IL4, P05112) IL-7 (IL7, P13232) IL-9 (IL9, P15248)

Endogenous antagonists IL-1 receptor antagonist (IL1RN, P18510) - - - -

Selective antagonists AF12198 [1], Ro264550 [3] - - - -

Nomenclature Interleukin 13 receptor, a2 Interleukin-15 receptor Interleukin-21 receptor Thymic stromal lymphopoietin receptor

HGNC, UniProt IL13RA2, Q14627 - -

Subunits Interleukin-2 receptor p subunit (Ligand-binding subunit), Interleukin 15 receptor, a subunit (Ligand-binding subunit), Interleukin-2 receptor y subunit (Other subunit) Interleukin 21 receptor (Ligand-binding subunit), Interleukin-2 receptor y subunit (Other subunit) Interleukin 7 receptor (Ligand-binding subunit), Cytokine receptor-like factor 2 (Other subunit)

Endogenous agonists - IL-15 (IL15, P40933) IL-21 (IL21, Q9HBE4) TSLP (TSLP, Q969D9)

Comment Decoy receptor that binds IL-13 (IL13, P35225) as a monomer.

IL-3 receptor family

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

Nomenclature Interleukin-3 receptor Interleukin-5 receptor Granulocyte macrophage colony-stimulating factor receptor

Subunits Interleukin 3 receptor, a subunit (Ligand-binding subunit), Cytokine receptor common p subunit (Other subunit) Interleukin 5 receptor, a subunit (Ligand-binding subunit), Cytokine receptor common p subunit (Other subunit) GM-CSF receptor, a subunit (Ligand-binding subunit), Cytokine receptor common p subunit (Other subunit)

Endogenous agonists IL-3 (IL3, P08700) IL-5 (IL5, P05113) G-CSF (CSF3, P09919), GM-CSF (CSF2, P04141)

Selective antagonists YM90709 [2]

IL-6 receptor family

Overview: The IL-6 receptor family signal through a ternary receptor complex consisting of the cognate receptor and either the IL-6 signal transducer gp130 (IL6ST, P40189) or the oncostatin M-specific receptor, p subunit (OSMR, Q99650), which then activates the JAK/STAT, Ras/Raf/MAPK and PI 3-kinase/PKB signalling modules. Unusually amongst the cytokine receptors, the CNTF receptor is a glycerophosphatidylinositol-linked protein.

Nomenclature Interleukin-6 receptor Interleukin-11 receptor Interleukin-31 receptor Ciliary neutrophic factor receptor

Subunits Interleukin-6 receptor, a subunit Interleukin-11 receptor, a subunit Interleukin-31 receptor, a subunit Ciliary neurotrophic factor receptor a subunit

(Ligand-binding subunit), Interleukin-6 (Ligand-binding subunit), Interleukin-6 (Ligand-binding subunit), Oncostatin (Ligand-binding subunit), Leukemia inhibitory

receptor, p subunit (Other subunit) receptor, p subunit (Other subunit) M-specific receptor, p subunit (Other subunit) factor receptor (Other subunit), Interleukin-6 receptor, p subunit

Endogenous agonists IL-6 (IL6, P05231) IL-11 (IL11, P20809) IL-31 (IL31, Q6EBC2) CNTF (CNTF, P26441), CRCF1/CLCF1 heterodimer (CRLF1, CLCF1, O75462, Q9UBD9)

Nomenclature Leptin receptor Leukemia inhibitory factor receptor Oncostatin-M receptor Interleukin-27 receptor

HGNC, UniProt LEPR, P48357 - - -

Subunits Leukemia inhibitory factor receptor (Ligand-binding subunit), Interleukin-6 receptor, ß subunit (Other subunit) Oncostatin M-specific receptor, ß subunit (Ligand-binding subunit), Interleukin-6 receptor, ß subunit (Other subunit) Interleukin 27 receptor, alpha (Ligand-binding subunit), Interleukin-6 receptor, ß subunit (Other subunit)

Endogenous agonists leptin (LEP, P41159) CTF1 (CTF1, Q16619), LIF (LIF, P15018), OSM (OSM, P13725) OSM (OSM, P13725) IL-27 (IL27, EBI3, Q14213, Q8NEV9)

IL-12 receptor family

Overview: IL-12 receptors are a subfamily of the IL-6 receptor family. IL12RB1 is shared between receptors for IL-12 and IL-23;the functional agonist at IL-12 receptors is a heterodimer of IL-12A/IL-12B, while that for IL-23 receptors is a heterodimer of IL-12B/IL-23A.

Subunits

Nomenclature Interleukin-12 receptor, ß2 subunit Interleukin 23 receptor

HGNC, UniProt IL12RB2, Q99665 IL23R, Q5VWK5

Prolactin receptor family

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

Nomenclature Eythropoietin receptor Granulocyte colony-stimulating factor receptor Growth hormone receptor Prolactin receptor Thrombopoietin receptor

HGNC, UniProt EPOR, P19235 CSF3R, Q99062 GHR, P10912 PRLR, P16471 MPL, P40238

Endogenous agonists erythropoietin (EPO, P01588) G-CSF (CSF3, P09919) growth hormone 1 (GH1, P01241), growth hormone 2 (GH2, P01242) choriomammotropin (CSH1, CSH2, P01243), chorionic somatomammotropin hormone-like 1 (CSHL1, Q14406), prolactin (PRL, P01236) thrombopoietin (THPO, P40225)

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.

Interferon receptor family

Overview: The interferon receptor family includes receptors for type I (a, P k and ro) and type II (y) interferons. There are at least 13 different genesencoding IFN-Αsubunits in a cluster on human chromosome 9p22: a1 (IFNA1, P01562), a2 (IFNA2, P01563), a4 (IFNA4, P05014), a5 (IFNA5, P01569), a6 (IFNA6, P05013), a7 (IFNA7, P01567), a8 (IFNA8, P32881), a10 (IFNA10, P01566), a13 (IFNA13, P01562), a14 (IFNA14, P01570), a16 (IFNA16, P05015), a17 (IFNA17, P01571) and a21 (IFNA21, P01568).

Nomenclature Interferon-a/ß receptor Interferon-Y receptor

Subunits interferon a/ß receptor 1 (Ligand-binding subunit), Interferon a/ß receptor 2 (Other subunit) Interferon y receptor 1 (Ligand-binding subunit), Interferon y receptor 2 (Other subunit)

Endogenous agonists IFN-a10 (IFNA10, P01566), IFN-a1/13 (IFNA1, IFNA13, P01562), IFN-a14 (IFNA14, P01570), IFN-a16 (IFNA16, P05015), IFN-a17 (IFNA17, P01571), IFN-a2 (IFNA2, P01563), IFN-a21 (IFNA21, P01568), IFN-a4 (IFNA4, P05014), IFN-a5 (IFNA5, P01569), IFN-a6 (IFNA6, P05013), IFN-a7 (IFNA7, P01567), IFN-a8 (IFNA8, P32881), IFN-ß (IFNB1, P01574), IFN-K (IFNK, Q9P0W0), IFN-œ (IFNW1, P05000) IFN-y (IFNG, P01579)

IL-10 receptor family

Overview: The IL-10 family of receptors are heterodimeric combinations of family members: IL10RA/IL10RB responds to IL-10;IL20RA/IL20RB responds to IL-19, IL-20 and IL-24;IL22RA1/IL20RB responds to IL-20 and IL-24;IL22RA1/IL10RB responds to IL-22;IL28RA/IL10RB responds to IL-28A, IL28B and IL-29.

Nomenclature Interleukin-10 receptor Interleukin-20 receptor Interleukin-22a1/20ß heteromer Interleukin-22a1/10ß heteromer Interleukin-22 receptor a2 Interferon-À receptor 1

HGNC, UniProt - - - - IL22RA2, Q969J5 -

Subunits Interleukin 10 receptor, a subunit (Ligand-binding subunit), Interleukin 10 receptor, p subunit (Other subunit) Interleukin 20 receptor, a subunit (Ligand-binding subunit), Interleukin 20 receptor, p subunit (Other subunit) Interleukin 20 receptor, ß subunit (Ligand-binding subunit), Interleukin 22 receptor, a1 subunit (Ligand-binding subunit) Interleukin 10 receptor, ß subunit (Ligand-binding subunit), Interleukin 22 receptor, a1 subunit (Ligand-binding subunit) Interferon-À receptor 1 (Ligand-binding subunit), Interleukin 10 receptor, p subunit (Other subunit)

Endogenous agonists IL-10 (IL10, P22301) IL-19 (IL19, Q9UHD0), IL-20 (IL20, Q9NYY1), IL-24 (IL24, Q13007) IL-20 (IL20, Q9NYY1), IL-24 (IL24, Q13007) IL-22 (IL22, Q9GZX6) IFN-À1 (IFNL1, Q8IU54), IFN-À2 (IFNL2, Q8IZJ0), IFN-À3 (IFNL3, Q8IZI9)

Comment Soluble decoy receptor that binds IL-22 (IL22, Q9GZX6) as a monomer

Immunoglobulin-like family of IL-1 receptors

Overview: The immunoglobulin-like family of IL-1 receptors are heterodimeric receptors made up of a cognate receptor subunit and an IL-1 receptor accessory protein, IL1RAP (Q9NPH3, also known as C3orf13, IL-1RAcP, IL1R3). They are characterised by extracellular immunoglobulin-like domains and an intracellular Toll/Interleukin-1R (TIR) domain.

Nomenclature Subunits

Endogenous agonists

Endogenous antagonists

Selective antagonists Comment

Interleukin-1 receptor, type I

Interleukin 1 receptor, type I (Ligand-binding subunit), IL-1 receptor accessory protein (Other subunit)

IL-1 a (IL1A, P01583), IL-1 ß (IL1B, P01584)

IL-1 receptor antagonist (IL1RN, P18510)

AF12198 [1]

Interleukin-33 receptor

Interleukin-1 receptor-like 1 (Ligand-binding subunit), IL-1 receptor accessory protein (Other subunit)

IL-33 (IL33, 095760)

Interleukin-36 receptor

Interleukin-1 receptor-like 2 (Ligand-binding subunit), IL-1 receptor accessory protein (Other subunit)

IL-36a (IL36A, Q9UHA7), IL-36ß (IL36B, Q9NZH7), IL-36y (IL36G, Q9NZH8),

IL-36 receptor antagonist (IL36RN, Q9UBH0)

IL-36 receptor antagonist (IL36RN, Q9UBH0) is a highly specific antagonist of the response to IL-36y (IL36G, Q9NZH8)

Interleukin-1 receptor, type II

Interleukin 1 receptor, type II (Ligand-binding subunit), IL-1 receptor accessory protein (Other subunit)

Interleukin-18 receptor Interleukin-18 1

(Ligand-binding subunit), IL-18 receptor accessory protein (Other subunit)

IL-18 (IL18, Q14116), IL-37 (IL37, Q9NZH6)

Decoy receptor that binds IL-1 a -(IL1A, P01583), IL-1 p (IL1B, P01584) and IL-1 receptor antagonist (IL1RN, P18510)

IL-17 receptor family

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

Nomenclature Interleukin-17 receptor Interleukin-25 receptor Interleukin-17C receptor Interleukin-17 receptor D

HGNC, UniProt - - - IL17RD, Q8NFM7

Subunits Interleukin 17 receptor A (Ligand-binding subunit), interleukin 17 receptor C (Other subunit) Interleukin 17 receptor B (Ligand-binding subunit), Interleukin 17 receptor A (Other subunit) Interleukin 17 receptor E (Ligand-binding subunit), Interleukin 17 receptor A (Other subunit)

Endogenous agonists IL-17A (IL17A, Q16552), IL-17A/IL-17F (IL17F, IL17A, Q16552, Q96PD4), IL-17F (IL17F, Q96PD4) IL-17B (IL17B, Q9UHF5), IL-25 (IL25, Q9H293) IL-17C (IL17C, Q9P0M4) The endogenous agonist for this receptor is unknown

Further reading

Broughton SE, Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA, Bonder CS, Lopez AF, Parker MW. (2012) The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol Rev 250: 277-302. [PMID:23046136] Chang SH, Dong C. (2011) Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 23: 1069-1075. [PMID:21130872] Donnelly RP, Dickensheets H, O'Brien TR. (2011) Interferon-lambda and therapy for chronic

hepatitis C virus infection. Trends Immunol 32: 443-450. [PMID:21820962] George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. (2012) Pharmacology and therapeutic

potential of interferons. Pharmacol Ther 135: 44-53. [PMID:22484806] Gibbert K, Schlaak JF, Yang D, Dittmer U. (2013) IFN-a subtypes: distinct biological activities in

anti-viral therapy. Br J Pharmacol 168: 1048-1058. [PMID:23072338] Mackall CL, Fry TJ, Gress RE. (2011) Harnessing the biology of IL-7 for therapeutic application. Nat

Rev Immunol 11: 330-342. [PMID:21508983] Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. (2012) IL-6/IL-6 receptor system and its

role in physiological and pathological conditions. Clin Sci 122: 143-159. [PMID:22029668] Miller AM, Liew FY. (2011) The IL-33/ST2 pathway-A new therapeutic target in cardiovascular

disease. Pharmacol Ther 131: 179-186. [PMID:21356240] Miossec P, Kolls JK. (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug

Discov 11: 763-776. [PMID:23023676] Murugaiyan G, Saha B. (2013) IL-27 in tumor immunity and immunotherapy. Trends Mol Med 19:

108-116. [PMID:23306374] Palmer G, Gabay C. (2011) Interleukin-33 biology with potential insights into human diseases. Nat

Rev Rheumatol 7: 321-329. [PMID:21519352] Pappu R, Ramirez-Carrozzi V, Sambandam A. (2011) The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases. Immunology 134: 8-16. [PMID:21726218]

Pappu R, Rutz S, Ouyang W. (2012) Regulation of epithelial immunity by IL-17 family cytokines. Trends Immunol 33: 343-349. [PMID:22476048]

Parker D, Prince A. (2011) Type I interferon response to extracellular bacteria in the airway

epithelium. Trends Immunol 32: 582-588. [PMID:21996313] Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB. (2004) Interleukin-10 and related

cytokines and receptors. Annu Rev Immunol 22: 929-979. [PMID:15032600] Rincon M. (2012) Interleukin-6: from an inflammatory marker to a target for inflammatory diseases.

Trends Immunol 33: 571-577. [PMID:22883707] Rubino SJ, Geddes K, Girardin SE. (2012) Innate IL-17 and IL-22 responses to enteric bacterial

pathogens. Trends Immunol 33: 112-118. [PMID:22342740] Sato N, Miyajima A. (1994) Multimeric cytokine receptors: common versus specific functions. Curr

Opin Cell Biol 6: 174-179. [PMID:8024807] Schindler C, Levy DE, Decker T. (2007) JAK-STAT signaling: from interferons to cytokines. J Biol

Chem 282: 20059-20063. [PMID:17502367] Shevach EM. (2012) Application of IL-2 therapy to target T regulatory cell function. Trends Immunol

33: 626-632. [PMID:22951308] Steel JC, Waldmann TA, Morris JC. (2012) Interleukin-15 biology and its therapeutic implications in

cancer. Trends Pharmacol Sci 33: 35-41. [PMID:22032984] Tanaka T, Narazaki M, Kishimoto T. (2012) Therapeutic targeting of the interleukin-6 receptor. Annu

Rev Pharmacol Toxicol 52: 199-219. [PMID:21910626] van der Lely AJ, Kopchick JJ. (2006) Growth hormone receptor antagonists. Neuroendocrinology 83:

264-268. [PMID:17047392] Wojno ED, Hunter CA. (2012) New directions in the basic and translational biology of interleukin-

27. Trends Immunol 33: 91-97. [PMID:22177689] Zepp J, Wu L, Li X. (2011) IL-17 receptor signaling and T helper 17-mediated autoimmune demy-

elinating disease. Trends Immunol 32: 232-239. [PMID:21493143] Zhu S, Qian Y. (2012) IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin Sci 122: 487-511. [PMID:22324470]

GDNF receptor family

Overview: GDNF family receptors (provisional nomenclature) are extrinsic tyrosine kinase receptors. Ligand binding to the extracellular domain of the glycosylphosphatidylinositol-linked cell-surface receptors (tabulated below) activates a

transmembrane tyrosine kinase enzyme, RET (see Receptor Tyrosine Kinases). The endogenous ligands are typically dimeric, linked through disulphide bridges: glial cell-derived neurotrophic factor GDNF (GDNF, P39905) (211 aa);neurturin

NRTN (NRTN, Q99748), 197 aa);artemin (ARTN (ARTN, Q5T4W7), 237 aa) and PSPN (PSPN, 060542) (PSPN, 156 aa).

Nomenclature GDNF family receptor al GDNF family receptor a2 GDNF family receptor a3 GDNF family receptor a4

Common abbreviation GFRal GFRa2 GFRa3 GFRa4

HGNC, UniProt GFRA1, P56159 GFRA2, 000451 GFRA3, 060609 GFRA4, Q9GZZ7

Potency order GDNF (GDNF, P39905) > NRTN (NRTN, Q99748) > ARTN (ARTN, Q5T4W7) NRTN (NRTN, Q99748) > GDNF (GDNF, P39905) ARTN (ARTN, Q5T4W7) PSPN (PSPN, 060542)

Radioligands (Kd) [125I]GDNF (rat) (3x10-12 - 6.3x10-11 M) [4,6] - - -

Comments: Inhibitors of other receptor tyrosine kinases, such as semaxinib, which inhibits VEGF receptor function, may also inhibit Ret function [5]. 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, Watson JJ, Shoemark DK, Barua NU, Patel NK. (2013) GDNF, NGF and BDNF as therapeutic

options for neurodegeneration. Pharmacol Ther 138: 155-175. [PMID:23348013] Carnicella S, Ron D. (2009) GDNF-a potential target to treat addiction. Pharmacol Ther 122: 9-18. [PMID:19136027]

Liu H, Li X, Xu Q, Lv S, Li J, Ma Q. (2012) Role of glial cell line-derived neurotrophic factor in perineural invasion of pancreatic cancer. Biochim Biophys Acta 1826: 112-120. [PMID:22503821]

Mickiewicz AL, Kordower JH. (2011) GDNF family ligands: a potential future for Parkinson's disease

therapy. CNS Neurol Disord Drug Targets 10: 703-711. [PMID:21838676] Pascual A, Hidalgo-Figueroa M, Gómez-Díaz R, López-Barneo J. (2011) GDNF and protection of adult

central catecholaminergic neurons. J Mol Endocrinol 46: R83-R92. [PMID:21357726] Rangasamy SB, Soderstrom K, Bakay RA, Kordower JH. (2010) Neurotrophic factor therapy for Parkinson's disease. Prog Brain Res 184: 237-264. [PMID:20887879]

Integrins

Overview: Integrins (provisional nomenclature) are heterodi-meric entities, composed of a and P 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 a subunit, and if present (in a1, a2, a10, a11, aD, aE, aL, aM and aX), this I domain contains the ligand binding site. All P 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 P subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg2+ atom 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.

Nomenclature Subunits Ligands Selective inhibitors (pICso) Comment

a1 ß1 integrin, alpha 1 subunit, integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) collagen, laminin obtustatin (9.1) [11] -

a2ß1 integrin, alpha 2 subunit (CD49B, alpha 2 subunit of VLA-2 receptor), integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) collagen, laminin, thrombospondin TCI15 (7.9) [13]

aIIbß3 integrin, alpha 2b subunit (platelet glycoprotein lib of IIb/IIIa complex, antigen CD41), integrin, beta 3 subunit (platelet glycoprotein IIIa, antigen CD61) fibrinogen, fibronectin, von Willebrand factor, vitronectin, thrombospondin abciximab, eptifibatide, G4120 [12], GR144053, Syk inhibitor III [14], tirofiban

a4ß1 integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA-4 receptor), integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) fibronectin, VCAM-1, osteopontin, thrombospondin natalizumab, TCS2314, BIO1211 (8.3 - 9.0) [9] LDV-FITC is used as a probe at this receptor

aLß2 integrin, alpha L subunit (antigen CD11A(p180), lymphocyte function-associated antigen 1; alpha polypeptide), integrin, beta 2 subunit (complement component 3 receptor 3 and 4 subunit) ICAM-1, ICAM-2 efalizumab, A286982 (7.4 - 7.5) [10]

aVß3 integrin, alpha V subunit, integrin, beta 3 subunit (platelet glycoprotein IIIa, antigen CD61) vitronectin, fibronectin, fibrinogen, osteopontin, von Willebrand factor, thrombospondin, tenascin etaracizumab, echistatin (11.7) [8], P11 (11.6) [8], cilengitide (8.5) [7]

Subunits

Nomenclature HGNC, UniProt

integr n, alpha 1 subunit ITGA1, P56199

integr n, alpha 2 subunit (CD49B, alpha 2 subunit of VLA-2 receptor) ITGA2, P08514

integr n, alpha 2b subunit (platelet glycoprotein lib of IIb/IIIa complex, antigen CD41) ITGA2B, P17301

integr n, alpha 3 subunit (antigen CD49C, alpha 3 subunit of VLA-3 receptor) ITGA3, P26006

integr n, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA-4 receptor) ITGA4, P13612

integr n, alpha 5 subunit (fibronectin receptor, alpha polypeptide) ITGA5, P08648

integr n, alpha 6 subunit ITGA6, P23229

integr n, alpha 7 subunit ITGA7, Q13683

integr n, alpha 8 subunit ITGA8, P53708

integr n, alpha 9 subunit ITGA9, Q13797

integr n, alpha 10 subunit ITGA10, O75578

integr n, alpha 11 subunit ITGA11, Q9UKX5

integr n, alpha D subunit ITGAD, Q13349

integr n, alpha E subunit (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide) ITGAE, P38570

integr n, alpha L subunit (antigen CD11A(p180), lymphocyte function-associated antigen 1; alpha polypeptide) ITGAL, P20701

integr n, alpha M subunit (complement component 3 receptor 3 subunit) ITGAM, P11215

integr n, alpha V subunit ITGAV, P06756

integr n, alpha X subunit (complement component 3 receptor 4 subunit) ITGAX, P20702

Nomenclature HGNC, UniProt

integrin, beta 1 subunit (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) ITGB1, P05556

integrin, beta 2 subunit (complement component 3 receptor 3 and 4 subunit) ITGB2, P05107

integrin, beta 3 subunit (platelet glycoprotein IIIa, antigen CD61) ITGB3, P05106

integrin, beta 4 subunit ITGB4, P16144

integrin, beta 5 subunit ITGB5, P18084

integrin, beta 6 subunit ITGB6, P18564

integrin, beta 7 subunit ITGB7, P26010

integrin, beta 8 subunit ITGB8, P26012

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 fibro-blasts. Extensive post-translational processing is conducted by prolyl and lysyl hydroxylases, as well as transglutaminases. Over 40 genes for collagen-a subunits have been identified in the human genome. The collagen-binding integrins a1p1, a2p1, a10p1 and a11p1 recognise a range of triple-helical peptide motifs including GFOGER (O = hydroxyproline), a synthetic peptide.

Laminin is an extracellular glycoprotein composed of a, P and y chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to a1p1, a2p1, a3,p1, a7P1 and a6P4 integrins10.

Fibrinogen is a glycosylated hexamer composed of two a (FGA, P02671), two p (FGB, P02675) and two y (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 aIIbp3;proteolysis by thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation cascade.

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

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

Von Willebrand factor (VWF, P04275) is a glycoprotein synthe-sised in vascular endothelial cells as a disulphide-linked homodi-mer, 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 aIIbp3).

Further reading

Anthis NJ, Campbell ID. (2011) The tail of integrin activation. Trends Biochem Sci 36: 191-198. [PMID:21216149]

Bledzka K, Smyth SS, Plow EF. (2013) Integrin aIIbp3: from discovery to efficacious therapeutic

target. CircRes 112: 1189-1200. [PMID:23580774] Cavallaro U, Dejana E. (2011) Adhesion molecule signalling: not always a sticky business. Nat Rev

Mol Cell Biol 12: 189-197. [PMID:21346732] Cox D, Brennan M, Moran N. (2010) Integrins as therapeutic targets: lessons and opportunities. Nat

Rev Drug Discov 9: 804-820. [PMID:20885411] Hogg N, Patzak I, Willenbrock F. (2011) The insider's guide to leukocyte integrin signalling and

function. Nat Rev Immunol 11: 416-426. [PMID:21597477] Hu P, Luo BH. (2013) Integrin bi-directional signaling across the plasma membrane. J Cell Physiol

228: 306-312. [PMID:22767296] Humphries JD, Byron A, Humphries MJ. (2006) Integrin ligands at a glance. J Cell Sci 119 (Pt 19): 3901-3903. [PMID:16988024]

Ivaska J, Heino J. (2011) Cooperation between integrins and growth factor receptors in signaling

and endocytosis. Annu Rev Cell Dev Biol 27: 291-320. [PMID:21663443] Kim C, Ye F, Ginsberg MH. (2011) Regulation of integrin activation. Annu Rev Cell Dev Biol 27:

321-345. [PMID:21663444] Roca-Cusachs P, Iskratsch T, Sheetz MP. (2012) Finding the weakest link: exploring integrin-mediated mechanical molecular pathways. J Cell Sci 125 (Pt 13): 3025-3038. [PMID:22797926] Shattil SJ, Kim C, Ginsberg MH. (2010) The final steps of integrin activation: the end game. Nat Rev

Mol Cell Biol 11: 288-300. [PMID:20308986] Weber GF, Bjerke MA, DeSimone DW. (2011) Integrins and cadherins join forces to form adhesive

networks. J Cell Sci 124 (Pt 8): 1183-1193. [PMID:21444749] Wickström SA, Fässler R. (2011) Regulation of membrane traffic by integrin signaling. Trends Cell

Biol 21: 266-273. [PMID:21440440] Wu X, Reddy DS. (2012) Integrins as receptor targets for neurological disorders. Pharmacol Ther 134: 68-81. [PMID:22233753]

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 (ANP (NPPA, P01160)), brain natriuretic peptide (BNP (NPPB,

P16860)) and C-type natriuretic peptide (CNP (NPPC, P23582)). Another family member is GC-C, the receptor for guanylin (GUCA2A, Q02747) and uroguanylin (GUCA2B, Q16661). Family members have conserved ligand-binding, catalytic (guanylyl cyclase) and regulatory domains with the exception of NPR-C which has an extracellular binding domain homologous to that

of other NPRs, but with a truncated intracellular domain which appears to couple, via the Gi/o family of G-proteins, to activation of phospholipase C, inwardly-rectifying potassium channels and inhibition of adenylyl cyclase activity [25].

Nomenclature NPR-A NPR-B NPR-C guanylate cyclase 2C (heat stable enterotoxin receptor)

HGNC, UniProt NPR1, P16066 NPR2, P20594 NPR3, P17342 GUCY2C, P25092

Potency order ANP (NPPA, P01160) > BNP (NPPB, P16860) >> CNP (NPPC, P23582) [27] CNP (NPPC, P23582) >> ANP (NPPA, P01160) >> BNP (NPPB, P16860) [27] ANP (NPPA, P01160) > CNP (NPPC, P23582) > BNP (NPPB, P16860) [27] uroguanylin (GUCA2B, Q16661) > guanylin (GUCA2A, Q02747)

Endogenous agonists ANP (NPPA, P01160) (Selective) [26], BNP (NPPB, P16860) (Selective) [26] CNP (NPPC, P23582) (Selective) [27] osteocrin (OSTN, P61366) (Selective) [23] -

Selective agonists sANP [26] - cANF4-23 [22] E. coli heat-stable enterotoxin (STa), linaclotide [18]

Selective antagonists anantin [29], A-71915 (pK 9.2 - 9.5) [15], [Asu7,23']ß-ANP-(7-28) (pK 7.5) [21] monoclonal antibody 3G12 [17], [Ser11](N-CNP, C-ANP)pBNP2-15 [16] M372049 [19], AP811 (pK 9.3) [28] -

Radioligands (Kd) [125I]ANP [125I]CNP (human) [125I]ANP [125I]Sta

Comments: The polysaccharide obtained from fermentation of Aureobasidium species, HS142-1, acts as an antagonist at both NPR-A and NPR-B receptors [24]. GUCY2D (RetGCl, GC-E, Q02846) and GUCY2F (RetGC2, GC-F, P51841) are predominantly retinal guanylyl cyclase activities, which are inhibited by calcium ions acting through the guanylyl cyclase activating peptides GCAP1 (GUCA1A, 43080), GCAP2 (GUCA1B, Q9UMX6) and GCAP3 (GUCA1C, O95843) [20].

Further reading

Kuhn M. (2012) Endothelial actions of atrial and B-type natriuretic peptides. Br J Pharmacol 166:

522-531. [PMID:22220582] Misono KS, Philo JS, Arakawa T, Ogata CM, Qiu Y, Ogawa H, Young HS. (2011) Structure, signaling mechanism and regulation of the natriuretic peptide receptor guanylate cyclase. FEBS J 278: 1818-1829. [PMID:21375693] Pandey KN. (2011) The functional genomics of guanylyl cyclase/natriuretic peptide receptor-A: perspectives and paradigms. FEBS J 278: 1792-1807. [PMID:21375691]

Potter LR. (2011) Guanylyl cyclase structure, function and regulation. Cell Signal 23: 1921-1926. [PMID:21914472]

Potter LR. (2011) Natriuretic peptide metabolism, clearance and degradation. FEBS J 278:

1808-1817. [PMID:21375692] Potter LR. (2011) Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases. Pharmacol Ther 130: 71-82. [PMID:21185863]

Pattern Recognition receptors

Overview: Pattern recognition receptors (PRR, [42]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRR include both cell-surface and intracellular proteins, including toll-like receptors (TLR), nucleotide-binding oligomerization domain-like receptors (NLR,

also known as NOD-like receptors) and the mannose receptor family (ENSFM00250000004089). PRR 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 pathogen-associated molecular patterns, which includes peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids.

Toll-like receptor family

Overview: Members of this family 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, [43-44]). TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11 are cell-surface proteins, while other members are associated with intracellular organelles, signalling through the MyD88-dependent pathways (with

the exception of TLR3). As well as responding to exogenous infectious agents, it has been suggested that selected members of the family may be activated by endogenous ligands, such as hsp60 (HSPD1, P10809) [38].

Nomenclature HGNC, UniProt Agonists Comment

TLR1 TLR1, Q15399 - -

TLR2 TLR2, 060603 peptidoglycan [41,45] -

TLR3 TLR3, 015455 polyIC [30] -

TLR4 TLR4, 000206 LPS [39], taxol [36] eritoran (E5564) is a lipid A analogue, which has been described as a TLR4 antagonist [35]

TLR5 TLR5, 060602 flagellin [31] -

TLR6 TLR6, Q9Y2C9 - -

TLR7 TLR7, Q9NYK1 imiquimod [33], loxoribine [32], R848 [33] -

TLR8 TLR8, Q9NR97 imiquimod, R848 [33] -

TLR9 TLR9, Q9NR96 CpG [34] -

TLR10 TLR10, Q9BXR5 - -

TLR11 -, Q6R5P0 - Found in the mouse

NOD-like receptor family

Overview: Structural analysis has identified a common motif of a mid-peptide located nucleotide-binding and oligomerization (NACHT) domain, which allows division of NOD-like receptors into three subfamilies, NLRC (or NODs), NLRP (or NALP) and IPAF [40]. NLRC members are named on the basis of a sequence motif expressed at their N-termini, the caspase recruitment

domain (CARD), while NLRP members have a pyrin domain. NLRs express C-terminal leucine-rich regions which have regulatory function and appear to recognize the microbial products to which the NLRs respond. NLRC family members recruit a serine/threonine kinase RIPK2 (receptor-interacting serine/ threonine kinase 2, O43353, also known as CARD3, CARDIAK,

RICK, RIP2) leading to signalling through NFkB and MAP kinase. NLRP family members, upon activation, recruit adaptor proteins (e.g. ASC, also known as PYCARD, CARD5, TMS-1, Q9ULZ3). Activated NLRs associate in multiprotein complexes, known as inflammasomes [40], allowing the recruitment of caspases.

Nomenclature HGNC, UniProt Agonists Comment

NLRC1 NOD1, Q9Y239 meso-DAP -

NLRC2 NOD2, Q9HC29 muramyl dipeptide -

NLRC3 NLRC3, Q7RTR2 - -

NLRC5 NLRC5, Q86WI3 - -

NLRX1 NLRX1, Q86UT6 - -

CIITA CIITA, P33076 - -

NLRP1 NLRP1, Q9C000 muramyl dipeptide -

NLRP2 NLRP2, Q9NX02 - -

NLRP3 NLRP3, Q96P20 - Multiple virus particles have been shown to act as agonists, including Sendai and influenza

NLRP4 NLRP4, Q96MN2 - -

NLRP5 NLRP5, P59047 - -

NLRP6 NLRP6, P59044 - -

NLRP7 NLRP7, Q8WX94 - -

NLRP8 NLRP8, Q86W28 - -

NLRP9 NLRP9, Q7RTR0 - -

NLRP10 NLRP10, Q86W26 - -

NLRP11 NLRP11, P59045 - -

NLRP12 NLRP12, P59046 - -

NLRP13 NLRP13, Q86W25 - -

NLRP14 NLRP14, Q86W24 - -

IPAF NLRC4, Q9NPP4 - -

NAIP NAIP, Q13075 - -

Comments: NLRP3 has also been reported to respond to host-derived products, known as danger-associated molecular patterns, or DAMPs, including uric acid [37], ATP, L-glucose, hyaluronan and amyloid p (APP, P05067) [40].

Loss-of-function mutations of NLRP3 are associated with cold autoinflammatory and Muckle-Wells syndromes. Further reading

Barton GM, Kagan JC. (2009) A cell biological view of Toll-like receptor function: regulation through

compartmentalization. Nat Rev Immunol 9: 535-542. [PMID:19556980] Buchanan MM, Hutchinson M, Watkins LR, Yin H. (2010) Toll-like receptor 4 in CNS pathologies.

J Neurochem 114: 13-27. [PMID:20402965] Celis E. (2007) Toll-like receptor ligands energize peptide vaccines through multiple paths. Cancer Res 67: 7945-7947. [PMID:17804699]

Chao W. (2009) Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury

in the heart. Am J Physiol Heart Circ Physiol 296: H1-12. [PMID:19011041] Chiron D, Jego G, Pellat-Deuceunynck C. (2010) Toll-like receptors: expression and involvement in

multiple myeloma. Leuk Res 34: 1545-1550. [PMID:20594595] Downes CE, Crack PJ. (2010) Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS?. Br J Pharmacol 160: 1872-1888. [PMID:20649586]

Ehlers M, Ravetch JV. (2007) Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol 28: 74-79. [PMID:17197239] Garantziotis S, Hollingsworth JW, Zaas AK, Schwartz DA. (2008) The effect of toll-like receptors and

toll-like receptor genetics in human disease. Annu Rev Med 59: 343-359. [PMID:17845139] Hennessy EJ, Parker AE, O'Neill LA. (2010) Targeting Toll-like receptors: emerging therapeutics?. Nat

Rev Drug Discov 9: 293-307. [PMID:20380038] Hirsch I, Caux C, Hasan U, Bendriss-Vermare N, Olive D. (2010) Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer. Trends Immunol 31: 391-397. [PMID:20832362]

Hori M, Nishida K. (2008) Toll-like receptor signaling: defensive or offensive for the heart?. Circ Res

102: 137-139. [PMID:18239139] Kanzler H, Barrat FJ, Hessel EM, Coffman RL. (2007) Therapeutic targeting of innate immunity with

Toll-like receptor agonists and antagonists. Nat Med 13: 552-559. [PMID:17479101] Könner AC, Brüning JC. (2011) Toll-like receptors: linking inflammation to metabolism. Trends

Endocrinol Metab 22: 16-23. [PMID:20888253] Lecat A, Piette J, Legrand-Poels S. (2010) The protein Nod2: an innate receptor more complex than

previously assumed. Biochem Pharmacol 80: 2021-2031. [PMID:20643110] Li H, Sun B. (2007) Toll-like receptor 4 in atherosclerosis. J Cell Mol Med 11: 88-95. [PMID:17367503] Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP. (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158: 1007-1020. [PMID:18809468] Marshak-Rothstein A, Rifkin IR. (2007) Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol 25: 419-441. [PMID:17378763]

Monie TP, Bryant CE, Gay NJ. (2009) Activating immunity: lessons from the TLRs and NLRs. Trends Biochem Sci 34: 553-561. [PMID:19818630]

O'Neill LA, Bowie AG. (2007) The family of five: TIR-domain-containing adaptors in Toll-like

receptor signalling. Nat Rev Immunol 7: 353-364. [PMID:17457343] O'Neill LA, Sheedy FJ, McCoy CE. (2011) MicroRNAs: the fine-tuners of Toll-like receptor signalling.

Nat Rev Immunol 11: 163-175. [PMID:21331081] Sabroe I, Parker LC, Dower SK, Whyte MK. (2008) The role of TLR activation in inflammation.

J Pathol 214: 126-135. [PMID:18161748] Saitoh S, Miyake K. (2009) Regulatory molecules required for nucleotide-sensing Toll-like receptors.

Immunol Rev 227: 32-43. [PMID:19120473] Sanjuan MA, Milasta S, Green DR. (2009) Toll-like receptor signaling in the lysosomal pathways.

Immunol Rev 227: 203-220. [PMID:19120486] Schroder K, Tschopp J. (2010) The inflammasomes. Cell 140: 821-832. [PMID:20303873] Shaw PJ, Lamkanfi M, Kanneganti TD. (2010) NOD-like receptor (NLR) signaling beyond the

inflammasome. Eur J Immunol 40: 624-627. [PMID:20201016] Takeuchi O, Akira S. (2010) Pattern recognition receptors and inflammation. Cell 140: 805-820. [PMID:20303872]

Trinchieri G, Sher A. (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat

Rev Immunol 7: 179-190. [PMID:17318230] Wenzel J, Tormo D, Tuting T. (2008) Toll-like receptor-agonists in the treatment of skin cancer: history, current developments and future prospects. Handb Exp Pharmacol (183): 201-220. [PMID:18071661]

Werling D, Jann OC, Offord V, Glass EJ, Coffey TJ. (2009) Variation matters: TLR structure and species-specific pathogen recognition. Trends Immunol 30: 124-130. [PMID:19211304]

Receptor serine/threonine kinase (RSTK) family

Overview: Receptor serine/threonine kinases (RTSK), EC 2.7.11.30, respond to particular cytokines, the transforming growth factor p (TGFP) 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 hetero-tetrameric, where where both subunits express serine/threonine kinase activity. The type I receptor serine/threonine kinases (ENSFM00250000000213) 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. TGFp 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 TGFp/activin/nodal subfamily and the BMP/GDF (growth/ differentiation factor)/MIS (Mullerian inhibiting substance) subfamily. Ligands active at RSTKs appear to be generated as large precursors which undergo complex maturation processes [47]. Some are known to form disulphide-linked homo- and/or heter-odimeric complexes. Thus, inhibins are a subunits linked to a variety of p chains, while activins are combinations of p subunits.

Type I receptor serine/threonine kinases

Overview: The type I receptor serine/threonine kinases (ENSFM00250000000213) are also known as activin receptors or activin receptor-like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1-7).

Nomenclature activin A receptor type activin A receptor, bone morphogenetic activin A receptor, transforming growth bone morphogenetic activin A receptor,

II-like 1 type I protein receptor, type IA type IB factor, beta receptor 1 protein receptor, type IB type IC

Common abbreviation ALK1 ALK2 BMPR1A ALK4 TGFBR1 BMPR1B ALK7

HGNC, UniProt ACVRL1, P37023 ACVR1, Q04771 BMPR1A, P36894 ACVR1B, P36896 TGFBR1, P36897 BMPR1B, 000238 ACVR1C, Q8NER5

Type II receptor serine/threonine kinases

Nomenclature activin A receptor, type IIA activin A receptor, type IIB anti-Mullerian hormone receptor, type II bone morphogenetic protein receptor, type II (serine/threonine kinase) transforming growth factor, beta receptor II (70/80kDa)

Common abbreviation ActR2 ActR2B MISR2 BMPR2 TGFBR2

HGNC, UniProt ACVR2A, P27037 ACVR2B, Q13705 AMHR2, Q16671 BMPR2, Q13873 TGFBR2, P37173

Type III receptor serine/threonine kinases

Nomenclature transforming growth factor, beta receptor III

Common abbreviation TGFBR3

HGNC, UniProt TGFBR3, Q03167

RSTK functional heteromers

Nomenclature

Subunits

Coupling

Endogenous

agonists

Transforming growth factor p receptor

transforming growth factor, beta receptor 1 (Type I), transforming growth factor, beta receptor II (70/80kDa) (Type II), transforming growth factor, beta receptor III (Type III)

Smad2, Smad3 [48-49] TGFßl (TGFB1, P01137), TGFß2 (TGFB2, P61812), TGFß3 (TGFB3, P10600)

Bone morphogenetic protein receptors

activin A receptor type II-like 1 (Type I), activin A receptor, type I (Type I), bone morphogenetic protein receptor, type IA (Type I), bone morphogenetic protein receptor, type IB (Type I), activin A receptor, type IIA (Type II), activin A receptor, type IIB (Type II), bone morphogenetic protein receptor, type II (serine/threonine kinase) (Type II)

Smad1, Smad5, Smad8 [48-49] BMP-10 (BMP10, O95393), BMP-2 (BMP2, P12643), BMP-4 (BMP4, P12644), BMP-5 (BMP5, P22003), BMP-6 (BMP6, P22004), BMP-7 (BMP7, P18075), BMP-8A (BMP8A, Q7Z5Y6), BMP-8B (BMP8B, P34820), BMP-9 (GDF2, Q9UK05)

Growth/differentiation factor receptors

bone morphogenetic protein receptor, type IA (Type I), activin A receptor, type IB (Type I), transforming growth factor, beta receptor 1 (Type I), bone morphogenetic protein receptor, type IB (Type I), activin A receptor, type IC (Type I), activin A receptor, type IIA (Type II), activin A receptor, type IIB (Type II), bone morphogenetic protein receptor, type II (serine/threonine kinase) (Type II)

Smadl, Smad5, Smad8 [48-49] GDF1 (GDF1, P27539), GDF10 (GDF10, P55107), GDF9 (GDF9, 060383), GDF3 (GDF3, Q9NR23)

Activin receptors

activin A receptor, type IB (Type I), activin A receptor, type IC (Type I), activin A receptor, type IIA (Type II), activin A receptor, type IIB (Type II)

Smad2, Smad3 [49] inhibin ßA (INHBA, P08476), inhibin ßB (INHBB, P09529)

Anti-Müllerian hormone receptors

activin A receptor, type I (Type I), bone morphogenetic protein receptor, type IA (Type I), bone morphogenetic protein receptor, type IB (Type I), anti-Mullerian hormone receptor, type II (Type II)

Smad1, Smad5, Smad8 [48-49] Müllerian inhibiting substance (AMH, P03971)

Comments: A number of endogenous inhibitory ligands have been identified for RSTKs, including BMP3, inhibina, inhibinpC and inhibinpE.

An appraisal of small molecule inhibitors of TGFp and BMP signalling concluded that TGFp pathway inhibitors were more selective than BMP signalling inhibitors [50]. The authors confirmed the selectivity of SB505124 to inhibit TGFp signalling through ALK4, ALK5, ALK7 [46]. dorsomorphin inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [51].

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.

Nomenclature HGNC, UniProt Other names

Smad1 SMAD1, Q15797 JV4-1, MADH1, MADR1

Smad2 SMAD2, Q15796 JV18-1, MADH2, MADR2

Smad3 SMAD3, P84022 HsT17436, JV15-2, MADH3

Smad4 SMAD4, Q13485 DPC4, MADH4

Smad5 SMAD5, Q99717 Dwfc, JV5-1, MADH5

Smadб SMAD6, O43541 HsT17432, MADH6, MADH7

Smad7 SMAD7, 015105 MADH7, MADH8

SmadB SMAD9, 015198 MADH6, MADH9

Further reading

Ehrlich M, Horbelt D, Marom B, Knaus P, Henis YI. (2011) Homomeric and heteromeric complexes among TGF-ß and BMP receptors and their roles in signaling. Cell Signal 23: 1424-1432. [PMID:21515362]

Hinck AP. (2012) Structural studies of the TGF-ßs and their receptors - insights into evolution of the

TGF-ß superfamily. FEBS Lett 586: 1860-1870. [PMID:22651914] Massague J. (2012) TGFß signalling in context. Nat Rev Mol Cell Biol 13: 616-630. [PMID:22992590] Moustakas A, Heldin CH. (2009) The regulation of TGFbeta signal transduction. Development 136: 3699-3714. [PMID:19855013]

Rider CC, Mulloy B. (2010) Bone morphogenetic protein and growth differentiation factor cytokine

families and their protein antagonists. Biochem J 429: 1-12. [PMID:20545624] Santibanez JF, Quintanilla M, Bernabeu C. (2011) TGF-ß/TGF-ß receptor system and its role in

physiological and pathological conditions. Clin Sci 121: 233-251. [PMID:21615335] Xu P, Liu J, Derynck R. (2012) Post-translational regulation of TGF-ß receptor and Smad signaling. FEBS Lett 586: 1871-1884. [PMID:22617150]

Receptor tyrosine kinases

Overview: Receptor tyrosine kinases (RTKs, EC 2.7.10.1), a family of cell-surface receptors, which transduce signals to poly-peptide 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 [55,65,82]. In the human genome, 58 RTKs have been identified, which fall into 20 families [70].

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 trans-duction pathways, including phospholipase C-y, mitogen-activated protein kinases and phosphatidylinositol 3-kinase [82].

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

Overview: ErbB family receptors are Class I receptor tyrosine kinases [65]. ERBB2 (also known as HER-2 or NEU;£RBB2, P04626) appears to act as an essential partner for the other members of the family without itself being activated by a cognate

ligand [66]. 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 Common abbreviation HGNC, UniProt Endogenous ligands

epidermal growth factor receptor EGFR EGFR, P00533 amphiregulin (AREG, AREGB, P15514), betacellulin (BTC, P35070), EGF (EGF, P01133), epigen (EPGN, Q6UW88), epiregulin (EREG, 014944), HB-EGF (HBEGF, Q99075), TGFa (TGFA, P01135)

v-erb-b2 avian erythroblastic leukemia HER3 ERBB3, P21860 NRG-1 (NRG1, Q02297), NRG-2 (NRG2, 014511)

viral oncogene homolog 3

v-erb-b2 avian erythroblastic leukemia HER4 ERBB4, Q15303 betacellulin (BTC, P35070), epiregulin (EREG, 014944), HB-EGF (HBEGF, Q99075),

viral oncogene homolog 4 NRG-1 (NRG1, Q02297), NRG-2 (NRG2, 014511), NRG-3 (NRG3, P56975), NRG-4 (NRG4, Q8WWG1)

Comments: [125I]EGF (human) has been used to label the ErbB1 EGF receptor. The extracellular domain of ErbB2 can be targetted by the antibodies trastuzumab and pertuzumab to inhibit ErbB family action. The intracellular ATP-binding site of the tyrosine kinase domain can be inhibited by GW583340 (7.9-8.0, [63]), gefitinib, erlotinib and tyrphostins AG879 and AG1478.

Type II RTKs: Insulin receptor family

Overview: The circulating peptide hormones insulin (INS, P01308) and the related insulin-like growth factors (IGF) activate Class II receptor tyrosine kinases [65], 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 Insulin receptor-related receptor

Common abbreviation InsR IGF1R IRR

HGNC, UniProt INSR, P06213 IGF1R, P08069 INSRR, P14616

Endogenous ligands insulin (INS, P01308) IGF1 (IGF1, P05019), IGF2 (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 trafficking role [72]. INSRR, which has a much more

discrete localization, being predominant in the kidney [69], 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 [56], while BMS-536924 inhibits both the insulin receptor and the insulinlike growth factor receptor [85].

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

Overview: Type III RTKs include PDGFR, CSF-1R (Ems), Kit and FLT3, which function as homo- or heterodimers. Endogenous ligands of PDGF receptors are homo- or heterodimeric: PDGFA, PDGFB, VEGFE and PDGFD 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.

Nomenclature platelet-derived growth factor platelet-derived growth factor v-kit Hardy-Zuckerman 4 feline colony stimulating factor 1 fms-related tyrosine kinase 3

receptor, alpha polypeptide receptor, beta polypeptide sarcoma viral oncogene homolog receptor

Common abbreviation PDGFRa PDGFRß Kit CSFR FLT3

HGNC, UniProt PDGFRA, P16234 PDGFRB, P09619 KIT, P10721 CSF1R, P07333 FLT3, P36888

Endogenous ligands PDGF PDGF SCF (KITLG, P21583) G-CSF (CSF3, P09919), GM-CSF (CSF2, P04141), M-CSF (CSF1, P09603) FLT3L (FLT3LG, P49771)

Comment 5'-fluoroindirubinoxime has been described as a selective FLT3 inhibitor [57]

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 [78];5'-fluoroindirubinoxime has been described as a selective FLT3 inhibitor [53].

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

Overview: VEGF receptors are homo- and heterodimeric proteins, which are characterized by seven Ig-like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lym-phangiogenesis;as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants

of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non-signalling entity. Ligands at VEGF receptors are typically homodimeric. VEGFA (VEGFA, P15692) is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. VEGFB (VEGFB, P49765)

and placental growth factor activate VEGFR1 homodimers, while VEGFC (VEGFC, P49767) and VEGFD (FIGF, O43915) activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.

Nomenclature fms-related tyrosine kinase 1 kinase insert domain receptor (a type III receptor tyrosine kinase) fms-related tyrosine kinase 4

Common abbreviation VEGFR-1 VEGFR-2 VEGFR-3

HGNC, UniProt FLT1, P17948 KDR, P35968 FLT4, P35916

Endogenous ligands VEGFA (VEGFA, P15692), VEGFB (VEGFB, P49765) VEGFA (VEGFA, P15692), VEGFC (VEGFC, P49767), VEGFE (PDGFC, Q9NRA1) VEGFC (VEGFC, P49767), VEGFD (FIGF, O43915), VEGFE (PDGFC, Q9NRA1)

Comments: The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [62], Ki8751 [68] and ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity [84] are described as VEGFR2-selective tyrosine kinase inhibitors. Bevacizumab is a monoclonal antibody directed against VEGF-A, used clinically for the treatment of certain metastatic cancers; an antibody fragment has been used for wet age-related macular degeneration.

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

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 [61]. 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 [83].

Nomenclature Common abbreviation HGNC, UniProt Endogenous ligands

fibroblast growth factor receptor 1 FGFR1

FGFR1, P11362

FGF-1 (FGF1, P05230), FGF-2 (FGF2, P09038), FGF-4 (FGF4, P08620) > FGF-5 (FGF5, P12034), FGF-6 (FGF6, P10767) [77]

fibroblast growth factor receptor 2 FGFR2

FGFR2, P21802

FGF-1 (FGF1, P05230) > FGF-4 (FGF4, P08620), FGF-7 (FGF7, P21781), FGF-9 (FGF9, P31371) > FGF-2 (FGF2, P09038), FGF-6 (FGF6, P10767) [77]

fibroblast growth factor receptor 3 FGFR3

FGFR3, P22607

FGF-1 (FGF1, P05230), FGF-2 (FGF2, P09038), FGF-9 (FGF9, P31371) > FGF-4 (FGF4, P08620), FGF-8 (FGF8, P55075) [77]

fibroblast growth factor receptor 4 FGFR4

FGFR4, P22455

FGF-1 (FGF1, P05230), FGF-2 (FGF2, P09038), FGF-4 (FGF4, P08620), FGF-9 (FGF9, P31371) > FGF-6 (FGF6, P10767), FGF-8 (FGF8, P55075) [77]

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 [71,87]. PD161570 is an FGFR tyrosine kinase inhibitor [54], while PD173074 has been described to inhibit FGFR1 and FGFR3 [80].

Type VII RTKs: Neurotrophin receptor/Trk family

Overview: 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 kB (NF-kB) activation. Both trkA and trkB contain two leucine-rich regions and can exist in monomeric or dimeric forms.

Nomenclature neurotrophic tyrosine kinase, receptor, type 1 neurotrophic tyrosine kinase, receptor, type 2 neurotrophic tyrosine kinase, receptor, type 3

Common abbreviation trkA trkB trkC

HGNC, UniProt NTRK1, P04629 NTRK2, Q16620 NTRK3, Q16288

Endogenous ligands NGF (NGF, P01138) > NT-3 (NTF3, P20783) BDNF (BDNF, P23560),NT-4 (NTF4, P34130) > NT-3 (NTF3, P20783) NT-3 (NTF3, P20783)

Comments: [125I]NGF (human) and [125I]BDNF have been used to label the trkA and trkB receptor, respectively. p75 influences the binding of NGF (NGF, P01138) and NT-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 NT-3 (NTF3, P20783) with comparable affinity to trkC [60].

Small molecule agonists of trkB have been described, including LM22A4 [73], while ANA12 has been described as a non-

competitive antagonist of BDNF binding to trkB [56]. GNF5837 is a family-selective tyrosine kinase inhibitor [52], while the tyros-ine kinase activity of the trkA receptor can be inhibited by GW441756 (p:o50= 8.7, [86]) and tyrphostin AG879 [76].

Type VIII RTKs: ROR family

Overview: Members of the ROR family (ENSFM00510000502747) 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 [67].

Nomenclature Common abbreviation HGNC, UniProt

receptor tyrosine kinase-like orphan receptor 1 ROR1

ROR1, Q01973

receptor tyrosine kinase-like orphan receptor 2 ROR2

ROR2, Q01974

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 heter-odimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and

inhibited by HGF-inhibitor 1, a serine protease inhibitor. MST1, the ligand of RON, is two disulphide-linked peptide chains generated by proteolysis of a single gene product.

Nomenclature met proto-oncogene macrophage stimulating 1 receptor (c-met-related tyrosine kinase)

Common abbreviation Met Ron

HGNC, UniProt MET, P08581 MST1R, Q04912

Endogenous ligands HGF (HGF, P14210) MST1 (MST1, P09603)

Comments: PF04217903 is a selective Met tyrosine kinase inhibitor [58]. SU11274 is an inhibitor of the HGF receptor [79], with the possibility of further targets [53].

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

Overview: Members of this RTK family (ENSFM00500000269872) represented a novel structural motif, when sequenced. The ligands for this family, Gas6 (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 AXL receptor tyrosine kinase TYRO3 protein tyrosine kinase c-mer proto-oncogene tyrosine kinase

Common abbreviation Axl Tyro3 Mer

HGNC, UniProt AXL, P30530 TYRO3, Q06418 MERTK, Q12866

Endogenous ligands Gas6 (GAS6, Q14393) [75], protein S (PROS1, P07225) [81] Gas6 (GAS6, Q14393) [75], protein S (PROS1, P07225) [81] Gas6 (GAS6, Q14393) [75]

Comments: AXL tyrosine kinase inhibitors have been described [74].

Type XII RTKs: TIE family of angiopoietin receptors

Overview: The TIE family were initially associated with formation of blood vessels. Endogenous ligands are angiopoietin-1 (ANGPT1, Q15389), angiopoietin-2 (ANGPT2, O15123), and angiopoietin-4 (ANGPT4, Q9Y264). angiopoietin-2 (ANGPT2, O15123) appears to act as an endogenous antagonist of angiopoietin-1 function.

Nomenclature tyrosine kinase with immunoglobulin-like and EGF-like domains 1 TEK tyrosine kinase, endothelial

Common abbreviation TIE1 TIE2

HGNC, UniProt TIE1, P35590 TEK, Q02763

Endogenous ligands - angiopoietin-1 (ANGPT1, Q15389), angiopoietin-4 (ANGPT4, Q9Y264)

Type XIII RTKs: Ephrin receptor family

Overview: Ephrin receptors (ENSFM00250000000121) 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 (EFNA1 (EFNA1, P20827), EFNA2 (EFNA2, O43921), EFNA3 (EFNA3, P52797), EFNA4 (EFNA4, P52798) and EFNA5 (EFNA5, P52803)) and 1TM proteins for Ephrin B (ENSFM00250000002014: EFNB1 (EFNB1, P98172), EFNB2

(EFNB2, P52799) and EFNB3 (EFNB3, Q15768)), although the relationship between ligands and receptors has been incompletely defined.

Nomenclature EPH EPH EPH EPH EPH EPH EPH EPH EPH EPH EPH EPH EPH EPH

receptor receptor receptor receptor receptor receptor receptor receptor receptor receptor receptor receptor receptor receptor

A1 A2 A3 A4 A5 A6 A7 A8 A10 B1 B2 B3 B4 B6

Common abbreviation EphA1 EphA2 EphA3 EphA4 EphA5 EphA6 EphA7 EphA8 EphA10 EphB1 EphB2 EphB3 EphB4 EphB6

HGNC, UniProt EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1 , EPHB2, EPHB3, EPHB4, EPHB6,

P21709 P29317 P29320 P54764 P54756 Q9UF33 Q15375 P29322 Q5JZY3 P54762 P29323 P54753 P54760 O15197

Type XVI RTKs: DDR (collagen receptor) family

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).

Nomenclature Common abbreviation HGNC, UniProt

discoidin domain receptor tyrosine kinase 1 DDR1

DDR1, Q08345

discoidin domain receptor tyrosine kinase 2 DDR2

DDR2, Q16832

Comments: The tyrosine kinase inhibitors of DDR, imatinib and nilotinib, were identified from proteomic analysis [59].

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

Overview: The LTK family (ENSFM00500000270379) appear to lack endogenous ligands. LTK is subject to tissue-specific splice variation, which appears to generate products in distinct subcellular locations. Alk fusions derived from gene translocations are associated with large cell lymphomas and inflammatory myofibrilastic tumours.

Nomenclature leukocyte receptor tyrosine kinase anaplastic lymphoma receptor tyrosine kinase

Common abbreviation LTK ALK

HGNC, UniProt LTK, P29376 ALK, Q9UM73

Comment - crizotinib appears to be a selective ALK inhibitor acting on the tyrosine kinase activity [64]

Further reading

Alsina FC, Ledda F, Paratcha G. (2012) New insights into the control of neurotrophic growth factor receptor signaling: implications for nervous system development and repair. J Neurochem 123: 652-661. [PMID:22994539] Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. (2012) Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol 9: 16-32. [PMID:22124364]

Camidge DR, Doebele RC. (2012) Treating ALK-positive lung cancer-early successes and future

challenges. Nat Rev Clin Oncol 9: 268-277. [PMID:22473102] Chen Y, Fu AK, Ip NY. (2012) Eph receptors at synapses: implications in neurodegenerative diseases.

Cell Signal 24: 606-611. [PMID:22120527] Fu HL, Valiathan RR, Arkwright R, Sohail A, Mihai C, Kumarasiri M, Mahasenan KV, Mobashery S, Huang P, Agarwal G etal. (2013) Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling. J Biol Chem 288: 7430-7437. [PMID:23335507] Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. (2012) Targeting MET in cancer: rationale

and progress. Nat Rev Cancer 12: 89-103. [PMID:22270953] Goetz R, Mohammadi M. (2013) Exploring mechanisms of FGF signalling through the lens of

structural biology. NatRevMol Cell Biol 14: 166-180. [PMID:23403721] Guillemot F, Zimmer C. (2011) From cradle to grave: the multiple roles of fibroblast growth factors

in neural development. Neuron 71: 574-588. [PMID:21867876] Higashiyama S, Nanba D, Nakayama H, Inoue H, Fukuda S. (2011) Ectodomain shedding and remnant peptide signalling of EGFRs and their ligands. J Biochem 150: 15-22. [PMID:21610047] Ibanez CF, Simi A. (2012) p75 neurotrophin receptor signaling in nervous system injury and

degeneration: paradox and opportunity. Trends Neurosci 35: 431-440. [PMID:22503537] Koh GY. (2013) Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med 19:

31-39. [PMID:23182855] Larsen AK, Ouaret D, El Ouadrani K, Petitprez A. (2011) Targeting EGFR and VEGF(R) pathway

cross-talk in tumor survival and angiogenesis. Pharmacol Ther 131: 80-90. [PMID:21439312] Lefebvre J, Ancot F, Leroy C, Muharram G, Lemiere A, Tulasne D. (2012) Met degradation: more than one stone to shoot a receptor down. FASEB J 26: 1387-1399. [PMID:22223753]

Leitinger B. (2011) Transmembrane collagen receptors. Annu Rev Cell Dev Biol 27: 265-290. [PMID:21568710]

Lennartsson J, Ronnstrand L. (2012) Stem cell factor receptor/c-Kit: from basic science to clinical

implications. Physiol Rev 92: 1619-1649. [PMID:23073628] Liang G, Liu Z, Wu J, Cai Y, Li X. (2012) Anticancer molecules targeting fibroblast growth factor

receptors. Trends Pharmacol Sci 33: 531-541. [PMID:22884522] Lisle JE, Mertens-Walker I, Rutkowski R, Herington AC, Stephenson SA. (2013) Eph receptors and their ligands: promising molecular biomarkers and therapeutic targets in prostate cancer. Biochim Biophys Acta 1835: 243-257. [PMID:23396052] Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14: 401-416. [PMID:23674053]

Morandi A, Plaza-Menacho I, Isacke CM. (2011) RET in breast cancer: functional and therapeutic

implications. Trends Mol Med 17: 149-157. [PMID:21251878] Peters S, Adjei AA. (2012) MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol 9:

314-326. [PMID:22566105] Roskoski Jr R. (2013) Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and

pharmacological inhibition. Pharmacol Res 68: 68-94. [PMID:23201355] Sheffler-Collins SI, Dalva MB. (2012) EphBs: an integral link between synaptic function and syn-

aptopathies. Trends Neurosci 35: 293-304. [PMID:22516618] Shibuya M. (2013) Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem 153: 13-19. [PMID:23172303]

Turner CA, Watson SJ, Akil H. (2012) The fibroblast growth factor family: neuromodulation of

affective behavior. Neuron 76: 160-174. [PMID:23040813] Woo KV, Baldwin HS. (2011) Role of Tie1 in shear stress and atherosclerosis. Trends Cardiovasc Med

21: 118-123. [PMID:22681967] Yamanashi Y, Tezuka T, Yokoyama K. (2012) Activation of receptor protein-tyrosine kinases from the cytoplasmic compartment. J Biochem 151: 353-359. [PMID:22343747]

Receptor tyrosine phosphatases (RTP)

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.

Nomenclature HGNC, UniProt Putative endogenous ligands

RTP Type A PTPRA, P18433 -

RTP Type B PTPRB, P23467 -

RTP Type C PTPRC, P08575 galectin-1 (LGALS1, P09382) [93]

RTP Type D PTPRD, P23468 netrin-G3 ligand (LRRC4B, Q9NT99) [90]

RTP Type E PTPRE, P23469 -

RTP Type F PTPRF, P10586 netrin-G3 ligand (LRRC4B, Q9NT99) [90]

RTP Type G PTPRG, P23470 contactin-3 (CNTN3, Q9P232), contactin-4 (CNTN4, Q8IWV2), contactin-5 (CNTN5, O94779), contactin-6 (CNTN6, Q9UQ52) [88]

RTP Type H PTPRH, Q9HD43 -

RTP Type J PTPRJ, Q12913 -

RTP Type K PTPRK, Q15262 galectin-3 (LGALS3, P17931), galectin-3 binding protein (LGALS3BP, Q08380) [89]

RTP Type M PTPRM, P28827 -

RTP Type N PTPRN, Q16849 -

RTP Type N2 PTPRN2, Q92932 -

RTP Type O PTPRO, Q16827 -

RTP Type Q PTPRQ, Q9UMZ3 -

RTP Type R PTPRR, Q15256 -

RTP Type S PTPRS, Q13332 chondroitin sulphate proteoglycan 3 (NCAN, O14594), netrin-G3 ligand (LRRC4B, Q9NT99) [90,92]

RTP Type T PTPRT, O14522 -

RTP Type U PTPRU, Q92729 -

RTP Type Z1 PTPRZ1, P23471 contactin-1 (CNTN1, Q12860), pleiotrophin (PTN, C9JR52) (acts as a negative regulator) [88,91]

Further reading

Böhmer F, Szedlacsek S, Tabernero L, Ostman A, den HertogJ. (2013) Protein tyrosine phosphatase structure-function relationships in regulation and pathogenesis. FEBS J 280: 413-431. [PMID:22682070]

Dushek O, Goyette J, van der Merwe PA. (2012) Non-catalytic tyrosine-phosphorylated receptors.

Immunol Rev 250: 258-276. [PMID:23046135] He R, Zeng LF, He Y, Zhang S, Zhang ZY. (2013) Small molecule tools for functional interrogation of protein tyrosine phosphatases. FEBS J 280: 731-750. [PMID:22816879]

Julien SG, Dubé N, Hardy S, Tremblay ML. (2011) Inside the human cancer tyrosine phosphatome.

Nat Rev Cancer 11: 35-49. [PMID:21179176] Mohebiany AN, Nikolaienko RM, Bouyain S, Harroch S. (2013) Receptor-type tyrosine phosphatase

ligands: looking for the needle in the haystack. FEBS J 280: 388-400. [PMID:22682003] Sastry SK, Elferink LA. (2011) Checks and balances: interplay of RTKs and PTPs in cancer progression. Biochem Pharmacol 82: 435-440. [PMID:21704606]

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 super-family (TNFSF). Some homologues lacking transmembrane and cytoplasmic domains function as decoy receptors binding ligand without inducing cell signalling. Many of these receptors and

ligands function as multimeric entities. Signalling through these receptors is complex and involves interaction with cytoplasmic adaptor proteins (such as TRADD and TRAF1). Several of these receptors contain cytoplasmic motifs known as 'death domains', which upon activation serve to recruit death domain- and death effector domain-containing proteins crucial for the initiation of an apoptotic response. Additional signalling pathways include

the regulation of the nuclear factor kB or mitogen-activated protein kinase pathways. Pharmacological manipulation of these receptors is mainly enacted through chelating the endogenous agonists with humanised monoclonal antibodies (e.g. infliximab or adalimumab) or recombinant fusion proteins of IgG and soluble receptors (e.g. etanercept). Some mutated forms of TNF ligands are capable of selecting for different receptor subtypes.

Receptors

Nomenclature Systematic nomenclature Common abbreviation HGNC, UniProt Adaptor proteins Endogenous ligands Comment

tumor necrosis factor receptor 1 TNFRSF1A TNFR1 TNFRSF1A, P19438 TRADD TNFSF1 (LTA, P01374), TNF membrane form (TNF, P01375), TNF shed form (TNF, P01375) -

tumor necrosis factor receptor 2 TNFRSF1B TNFR2 TNFRSF1B, P20333 TRAF1, TRAF2, TRAF5 TNFSF1 (LTA, P01374), TNF membrane form (TNF, P01375) -

lymphotoxin p receptor TNFRSF3 - LTBR, P36941 TRAF3, TRAF4, TRAF5 LIGHT (TNFSF14, O43557), lymphotoxin ß2<* heterotrimer (LTA, LTB, Q06643, P01374) -

OX40 TNFRSF4 - TNFRSF4, P43489 TRAF1, TRAF2, TRAF3, TRAF5 0X-40 ligand (TNFSF4, P23510) -

CD40 TNFRSF5 - CD40, P25942 TRAF1, TRAF2, TRAF3, TRAF5, TRAF6 CD40 ligand (CD40LG, P29965) -

Fas TNFRSF6 - FAS, P25445 FADD Fas ligand (FASLG, P48023) -

CD27 TNFRSF7 - CD27, P26842 TRAF2, SIVA CD70 (CD70, P32970) -

CD30 TNFRSF8 - TNFRSF8, P28908 TRAF1, TRAF2, TRAF3, TRAF5 CD30 ligand (TNFSF8, P32971) -

4-1BB TNFRSF9 - TNFRSF9, Q07011 TRAF1, TRAF2, TRAF3 4-1BB ligand (TNFSF9, P41273) -

death receptor 4 TNFRSF10A DR4 TNFRSF10A, 000220 FADD TRAIL (TNFSF10, P50591) -

death receptor 5 TNFRSF10B DR5 TNFRSF10B, O14763 FADD TRAIL (TNFSF10, P50591) -

receptor activator of NF-kappa B TNFRSF11A RANK TNFRSF11A, Q9Y6Q6 TRAF1, TRAF2, TRAF3, TRAF5, TRAF6 RANK ligand (TNFSF11, 014788) -

osteoprotegerin TNFRSF11B OPG TNFRSF11B, 000300 Acts as a decoy receptor for RANK ligand (TNFSF11, O14788) and possibly for TRAIL (TNFSF10, P50591)

death receptor 3 TNFRSF25 DR3 TNFRSF25, Q93038 TRADD TL1A (TNFSF15, 095150) -

TWEAK receptor TNFRSF12A - TNFRSF12A, Q9NP84 TRAF1, TRAF2, TRAF3 TWEAK (TNFSF12, 043508) -

TACI TNFRSF13B TNFRSF13B, O14836 TRAF2, TRAF5, TRAF6 APRIL (TNFSF13, 075888), BAFF (TNFSF13B, Q9Y275)

Nomenclature Systematic nomenclature Common abbreviation HGNC, UniProt Adaptor proteins Endogenous ligands Comment

BAFF receptor TNFRSF13C BAFF-R TNFRSF13C, Q96RJ3 TRAF3 BAFF (TNFSF13B, Q9Y275) -

herpes virus entry mediator TNFRSF14 HVEM TNFRSF14, Q92956 TRAF2, TRAF3, TRAF5 BTLA (BTLA, Q7Z6A9), LIGHT (TNFSF14, O43557), TNFSF1 (LTA, P01374) -

nerve growth factor receptor TNFRSF16 - NGFR, P08138 TRAF2, TRAF4, TRAF6 BDNF (BDNF, P23560), NT-3 (NTF3, P20783), NT-4 (NTF4, P34130), NGF (NGF, P01138) -

B cell maturation antigen TNFRSF17 BCMA TNFRSF17, Q02223 TRAF1, TRAF2, TRAF3, TRAF5, TRAF6 APRIL (TNFSF13, O75888), BAFF (TNFSF13B, Q9Y275) -

glucocorticoid-induced TNF receptor TNFRSF18 GITR TNFRSF18, Q9Y5U5 TRAF1, TRAF2, TRAF3, SIVA TL6 (TNFSF18, Q9UNG2) -

toxicity and JNK inducer TNFRSF19 TAJ TNFRSF19, Q9NS68 TRAF1, TRAF2, TRAF3, TRAF5 TNFSF1 (LTA, P01374) -

RELT TNFRSF19L - RELT, Q969Z4 TRAF1 - -

death receptor 6 TNFRSF21 DR6 TNFRSF21, 075509 TRADD - -

ectodysplasin A2 isoform receptor TNFRS27 EDA2R, Q9HAV5 TRAF1, TRAF3, TRAF6 ectodysplasin A2 (EDA, Q92838) [94]

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 neuro-trophins nerve growth factor (NGF (NGF, P01138), P01138), brain-derived neurotrophic factor (BDNF (BDNF, P23560),

P23560), NT-3 (NTF3, P20783) (NTF3, P20783) and NT-4 (NTF4, P34130) (NTF4, P34130) are structurally unrelated to the TNF ligand superfamily but exert some of their actions through the "low affinity nerve growth factor receptor" (NGFR (TNFRSF16)) as well as through the TRK family of receptor tyrosine kinases.

The endogenous ligands for EDAR and EDA2R are, respectively, the membrane (Q92838[1-391]) and secreted (Q92838[160-391]) isoforms of Ectodysplasin-A (EDA, Q92838).

Further reading

Aggarwal BB. (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev

Immunol 3: 745-756. [PMID:12949498] Ashkenazi A. (2002) Targeting death and decoy receptors of the tumour-necrosis factor superfamily.

Nat Rev Cancer 2: 420-430. [PMID:12189384] Huang EJ, Reichardt LF. (2001) Neurotrophins: roles in neuronal development and function. Annu RevNeurosci 24: 677-736. [PMID:11520916]

Mahmood Z, Shukla Y. (2010) Death receptors: targets for cancer therapy. Exp Cell Res 316: 887-899. [PMID:20026107]

Rickert RC, Jellusova J, Miletic AV. (2011) Signaling by the tumor necrosis factor receptor super-

family in B-cell biology and disease. Immunol Rev 244: 115-133. [PMID:22017435] Tansey MG, Szymkowski DE. (2009) The TNF superfamily in 2009: new pathways, new indications, and new drugs. Drug Discov Today 14: 1082-1088. [PMID:19837186]

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