Catalytic Receptors

Catalytic receptors are cell-surface proteins, usually dimeric in nature, which encompass ligand binding and functional domains typically 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 it's 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. The fifth and final group are 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. NC-IUPHAR is currently considering nomenclature of catalytic receptors. It is recommended that nomenclature from the Human Genome Organisation Gene Nomenclature Committee (HGNC) is adopted where the precise complement of receptors is known (e.g. using heterologous expression). The alternative nomenclature recommended in the Guide to Receptors and Channels, Fifth Edition, may be considered as provisional. 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 Receptors and Channels, receptors for the TNF family (see Page S211), the TGF-β family (see Page S200) and the chemokines (see Page S39). Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. 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-oligomerization, 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, ENSFM00250000000777), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs, ENSFM00500000269705, ENSFM00500000269817). The activated homo- or heterodimeric STATs function principally as transcription factors in the nucleus. The IL-2 family of cytokines bind to heterodimeric receptors with ligand-selective α or β chains, and a common γ chain (γc) (IL2RG, ENSG00000147168, also known as CD132, CIDX, IMD4, severe combined immunodeficiency, SCIDX1). IL13RA2 acts as a substitute for γc producing a non-signalling complex; a decoy receptor. Endogenous agonists include IL-2 (ENSG00000109471, also known as T-cell growth factor, TCGF, aldesleukin), IL-4 (ENSG00000113520, also known as B-cell stimulatory factor 1, lymphocyte stimulatory factor 1, binetrakin, pitrakinra), IL-7 (ENSG00000104432), IL-9 (ENSG00000145839, also known as HP40, P40), IL-13 (ENSG00000169194), IL-15 (ENSG00000164136), IL-21 (ENSG00000138684, also known as ZA11) and thymic stromal lymphopoietin (TSLP, ENSG00000145777). Ro264550 has been described as a selective IL-2 receptor antagonist, which binds to IL-2 (Tilley et al. 1997). The IL-3 family signal through a receptor complex comprising of a ligand-specific α subunit and a common β chain (CSF2RB, ENSG00000100368, also known as CD131, IL3RB or IL5RB), which is shared between all members of this cytokine family. Endogenous agonists include IL-3 (ENSG00000164399, also known as multipotential colony-stimulating factor, hematopoietic growth factor, P-cell-stimulating factor, mast cell growth factor), IL-5 (ENSG00000113525, also known as EDF, TRF), GM-CSF (ENSG00000164400), and G-CSF (ENSG00000108342). YM90709 has been described as a selective IL-5 receptor antagonist (Morokata et al., 2002). The IL-6 family signal through a ternary receptor complex consisting of the cognate receptor and a homodimer of the IL-6 signal transducer gp130 (IL6ST, ENSG00000134352, also known as CD130, oncostatin M receptor), 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. CRLF1 (cytokine receptor-like factor 1, ENSG00000006016, also known as CISS, CISS1, CLF, CLF-1, NR6) acts as an endogenous antagonist for the CNTF receptor. Endogenous agonists include IL-6 (ENSG00000136244, also known as B-cell stimulatory factor 2, interferon β-2, hybridoma growth factor, CTL differentiation factor), IL-11 (ENSG00000095752, also known as adipogenesis inhibitory factor), ciliary neurotrophic factor (CNTF, ENSG00000242689), cardiotrophin-1 (CTF1, ENSG00000150281, also known as B-cell stimulatory factor 3, BSF3), cardiotrophin-like cytokine (CLCF1, ENSG00000175505), leptin (LEP, ENSG00000174697, also known as OB), leukemia inhibitory factor (LIF, ENSG00000128342, also known as cholinergic differentiation factor) and Oncostatin M (OSM, ENSG00000099985). The IL-12 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 or homodimer of IL-12B/IL-2B subunits, while that for IL-23 receptors is a heterodimer of IL-12A/IL-23A. Endogenous agonists include IL-12A (ENSG00000168811, also known as CLMF, IL-12A, NFSK, NKSF1, p35), IL-12B (ENSG00000113302, also known as natural killer cell stimulatory factor 2, cytotoxic lymphocyte maturation factor 2, p40) and IL-23 (ENSG00000110944). The prolactin receptor family is made up of homodimeric receptor tyrosine kinases. Endogenous agonists are large (∼200 aa) polypeptides, and include erythropoietin (EPO, ENSG00000130427), granulocyte macrophage colony-stimulating factor (GM-CSF, ENSG00000164400, also known as colony-stimulating factor, CSF, sargramostim, molgramostin), growth hormone 1 (GH1, ENSG00000189162), growth hormone 2 (GH2, ENSG00000136488, also known as placenta-specific growth hormone), choriomammotropin (CSH1, ENSG00000136487, also known as lactogen), thrombopoietin (TPO, ENSG00000090534, also known as megakaryocyte colony-stimulating factor, myeloproliferative leukemia virus oncogene ligand, C-mpl ligand, megakaryocyte growth and development factor, MGDF), chorionic somatomammotropin hormone 2 (CSH2, ENSG00000213218), chorionic somatomammotropin hormone-like 1 (CSHL, ENSG00000204414, also known as lactogen-like) and granulocyte colony stimulating factor (CSF3, ENSG00000108342, also known as G-CSF, pluripoietin, filgrastim, lenograstim). The interferon receptor family includes receptors for type I and type II interferons, that bind to heterodimeric receptors made up of IFNAR1/IFNAR2 or IFNGR1/IFNGR2, respectively. Endogenous agonists in man include IFN-α (IFNA1, ENSG00000197919), IFN-β (IFNB1, ENSG00000171855), IFN-γ (IFNG, ENSG00000111537), IFN-κ (IFNK, ENSG00000147896) and IFN-ω (IFNW1, ENSG00000177047). 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. Endogenous agonsits are IL-10 (ENSG00000136634), IL-19 (ENSG00000142224), IL-20 (ENSG00000162891), IL-22 (ENSG00000127318), IL-24 (ENSG00000162892), IL-28A (IL28A, ENSG00000183709, also known as IFN-λ2), IL-28B (IL28B, ENSG00000197110, also known as IFN-λ3), IL-29 (ENSG00000182393). 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, ENSG00000196083, also known as C3orf13, IL-1RAcP, IL1R3). IL1R2, the type II IL-1 receptor (ENSG00000115590, also known as CD121b, IL1RB), is a decoy receptor, while the IL-1 receptor antagonist (IL1RN, ENSG00000136689, also known as ICIL-1RA, IL1F3, IL1RA, IRAP) prevents IL-1 binding to the receptor. Analogues of IL1RAP have been identified in the human genome: IL-1 receptor accessory protein-like 1 protein (IL1RAPL1, ENSG00000169306, also known as IL1R8, IL1RAPL, MRX10, MRX21, MRX34, OPHN4 or TIGIRR-2), X-linked IL-1 receptor accessory protein-like 2 (IL1RAPL2, ENSG00000189108, also known as IL-1R9, IL1R9, IL1RAPL-2 or TIGIRR-1) and IL-18 receptor accessory protein-like (IL18RAP, ENSG00000115607, also known asAcPL, CD218b). Endogenous agonists are IL-1α (IL1A, ENSG00000115008, also known as IL-1 or IL-1F1), IL-1β (ENSG00000125538, also known as IL-1F2) and IL-18 (ENSG00000150782, also known as IFN-γ-inducing factor). AF12198 has been described as a selective Type I IL-1 receptor antagonist (Akeson et al., 1996). The IL17 receptor family appear to represent a distinct class of cytokine receptors with incompletely defined signalling. Endogenous agonists include IL-17A (ENSG00000112115, also known as cytotoxic T-lymphocyte-associated serine esterase 8; CTLA8). Abbreviations: AF12198, AcPheGluTrpThrProGlyTrpTyrGlnAzeTyrAlaLeuProLeu; CSF, colony stimulating factor; EPO, erythropoietin; GH, growth hormone; G-CSF, granulocyte colony-stimulating factor; GMCSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; LIF, leukemia inhibitory factor; OSM, oncostatin-M; PRL prolactin; Ro264550, N-[[(3R)-1-(aminoiminomethyl)-3-piperidinyl]acetyl]-4-(phenylethynyl)-L-phenylalanine methyl ester; STAT, signal transducers and activators of transcription; TPO, thrombopoietin; YM90709, 2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline Ben-Jonathan N, Hugo ER, Brandebourg TD, LaPensee CR (2006). Focus on prolactin as a metabolic hormone. Trends Endocrinol Metab17: 110–116. Ben-Jonathan N, LaPensee CR, LaPensee EW (2008). What can we learn from rodents about prolactin in humans? Endocr Rev29: 1–41. Constantinescu SN, Girardot M, Pecquet C (2008). Mining for JAK-STAT mutations in cancer. Trends Biochem Sci33: 122–131. Duncan MJ (2007). Circannual prolactin rhythms: calendar-like timer revealed in the pituitary gland. Trends Endocrinol Metab18: 259–260. Giustina A, Mazziotti G, Canalis E (2008). Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev29: 535–559. Grattan DR, Kokay IC (2008). Prolactin: a pleiotropic neuroendocrine hormone. J Neuroendocrinol20: 752–763. Holt RI, Sonksen PH (2008). Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol154: 542–556. van der Lely AJ, Kopchick JJ (2006). Growth hormone receptor antagonists. Neuroendocrinology83: 264–268. Li WX (2008). Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol18: 545–551. Lichanska AM, Waters MJ (2008). How growth hormone controls growth, obesity and sexual dimorphism. Trends Genet24: 41–47. Marcucci R, Romano M (2008). Thrombopoietin and its splicing variants: structure and functions in thrombopoiesis and beyond. Biochim Biophys Acta1782: 427–432. Moller N, Jorgensen JO (2009). Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev30: 152–177. Pilecka I, Whatmore A, van Hooft HR, Destenaves B, Clayton P (2007). Growth hormone signalling: sprouting links between pathways, human genetics and therapeutic options. Trends Endocrinol Metab18: 12–18. Schindler C, Levy DE, Decker T (2007). JAK-STAT signaling: from interferons to cytokines. J Biol Chem282: 20059–20063. Soares MJ, Konno T, Alam SM (2007). The prolactin family: effectors of pregnancy-dependent adaptations. Trends Endocrinol Metab18: 114–121. Takano H, Ueda K, Hasegawa H, Komuro I (2007). G-CSF therapy for acute myocardial infarction. Trends Pharmacol Sci28: 512–517. Tworoger SS, Hankinson SE (2006). Prolactin and breast cancer risk. Cancer Lett243: 160–169. Velloso CP (2008). Regulation of muscle mass by growth hormone and IGF-I. Br J Pharmacol154: 557–568. Ward AC (2007). The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease. Front Biosci12: 608–618. Xu J, Messina JL (2009). Crosstalk between growth hormone and insulin signaling. Vitam Horm80: 125–153. Overview: GDNF family receptors (ENSFM00500000269996) 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 (Rearranged during transfection, ENSG00000165731). The endogenous ligands are typically dimeric, linked through disulphide bridges: glial cell-derived neurotrophic factor (GDNF, 211 aa, ENSG00000168621); neurturin (NRTN, 197 aa, ENSG00000171119); artemin (ARTN, 237 aa, ENSG00000117407) and persephin (PSPN, 156 aa, ENSG00000125650). Inhibitors of other receptor tyrosine kinases, such as semaxinib, which inhibits VEGF receptor function, may also inhibit Ret function (Mologni et al., 2006). 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. Bespalov MM, Saarma M (2007). GDNF family receptor complexes are emerging drug targets. Trends Pharmacol Sci28: 68–74. Carnicella S, Ron D (2009). GDNF – a potential target to treat addiction. Pharmacol Ther122: 9–18. Ernsberger U (2008). The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons. Cell Tissue Res333: 353–371. Paratcha G, Ledda F (2008). GDNF and GFRα: a versatile molecular complex for developing neurons. Trends Neurosci31: 384–391. Rangasamy SB, Soderstrom K, Bakay RA, Kordower JH (2010). Neurotrophic factor therapy for Parkinson's disease. Prog Brain Res184: 237–264. Schueler-Furman O, Glick E, Segovia J, Linial M (2006). Is GAS1 a co-receptor for the GDNF family of ligands? Trends Pharmacol Sci27: 72–77. Overview: Natriuretic peptide receptors are a family (ENSFM00250000000198) 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, ENSG00000175206), brain natriuretic peptide (BNP, ENSG00000120937) and C-type natriuretic peptide (CNP, ENSG00000163273). Another family member is GC-C, the receptor for guanylin (ENSG00000113389) and uroguanylin (ENSG00000044012). 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 (Murthy and Makhlouf, 1999). The polysaccharide obtained from fermentation of Aureobasidium species, HS142-1, acts as an antagonist at both NPR-A and NPR-B receptors (Morishita et al., 1991). Gucy2D (RetGC1, GC-E, ENSG00000132518) and Gucy2F (RetGC2, GC-F, ENSG00000101890) are predominantly retinal guanylyl cyclase activities, which are inhibited by calcium ions acting through the guanylyl cyclase activating peptides GCAP1 (GUCA1A, ENSG00000048545), GCAP2 (GUCA1B, ENSG00000112599) and GCAP3 (GUCA1C, ENSG00000138472) (see Hunt et al., 2010). Abbreviations: A71915, ([Arg6,Cha8]ANP6–15-d-Tic-Arg-Cys-NH2; anantin, cyclo(Gly-Phe-Ile-Gly-Trp-Gly-Asn-β-Asp)-Ile-Phe-Gly-His-Tyr-Ser-Gly-Asp-Phe; AP811, (s)-N2-([4-{(2-naphthalenylcarbonyl)amino}phenyl]acetyl)-l-arginyl-l-isoleucyl-l-α-aspartyl-N-(2-methylbutyl)-l-argininamide; [Asu7,23′]-β-ANP(7–28), an antiparallel dimer linked by 7-23′ and 7′-23 disulphide bonds (Asu, l-α-aminosuberic acid); cANF4–23, des[Gln18,Ser19,Gly20,Leu21,Gly22]ANP4–23-NH2; HS142-1, Aureobasidium-derived polysaccharide; M372049, see Chauhan et al. (2003) for structure; sANP, [G9T, R11S, G16R]ANP Hunt DM, Buch P, Michaelides M. (2010) Guanylate cyclases and associated activator proteins in retinal disease. Mol Cell Biochem334: 157–168. van Kimmenade RR, Januzzi JL, Jr. (2009). The evolution of the natriuretic peptides – Current applications in human and animal medicine. J Vet Cardiol11 (Suppl. 1): S9–21. Kishimoto I, Tokudome T, Nakao K, Kangawa K (2011). Natriuretic peptide system: an overview of studies using genetically engineered animal models. FEBS J278: 1830–1841. Kuhn M (2009). Function and dysfunction of mammalian membrane guanylyl cyclase receptors: lessons from genetic mouse models and implications for human diseases. Handb Exp Pharmacol191: 47–69. Lanfear DE (2010). Genetic variation in the natriuretic peptide system and heart failure. Heart Fail Rev15: 219–228. Li P, Lin JE, Marszlowicz GP, Valentino MA, Chang C, Schulz S et al. (2009). GCC signaling in colorectal cancer: is colorectal cancer a paracrine deficiency syndrome? Drug News Perspect22: 313–318. Misono KS, Philo JS, Arakawa T, Ogata CM, Qiu Y, Ogawa H et al. (2011). Structure, signaling mechanism and regulation of the natriuretic peptide receptor guanylate cyclase. FEBS J278: 1818–1829. Pandey KN (2011). The functional genomics of guanylyl cyclase/natriuretic peptide receptor-A: perspectives and paradigms. FEBS J278: 1792–1807. Potter LR (2011). Natriuretic peptide metabolism, clearance and degradation. FEBS J278: 1808–1817. Potter LR, Yoder AR, Flora DR, (2009). Natriuretic their receptors, functions and therapeutic Handb Exp Pharmacol191: S, S, A, C, A, M (2010). a of the natriuretic peptide family with implications in human diseases. 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These to the and as complexes to The type I receptor serine/threonine kinases are also known as receptors or receptor-like kinases, for which a nomenclature has been The type II receptor serine/threonine kinases identified as mammalian of genes and may be and and and complexes with for binding of with both receptors and Endogenous agonists are characterized by conserved and are subfamilies on the of and signalling the and the at appear to be as large which complex maturation (see Li and are known to homo- heterodimeric are α linked to a of β chains, while are combinations of β of family members complexes of receptor II or receptor with or and to and (see and of BMP family members complexes of BMP receptor 2, receptor or receptor with