Volume 147, Issue S3 p. S127-S133
Free Access


First published: 10 February 2009
Citations: 26

ErbB family

Overview: ErbB family receptors (ENSF00000000164, provisional nomenclature) are cell-surface receptors, which, when activated by members of the epidermal growth factor (EGF) family, activate a transmembrane tyrosine kinase activity (E.C. leading to the stimulation of multiple signal transduction pathways (see Yarden and Sliwkowski, 2001). ErbB2 (also known as HER-2 or NEU, ENSG00000141736) appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand (Graus-Porta et al., 1997).

Ligands of the ErbB family of receptors are peptides including EGF (ENSG00000138798), amphiregulin (also known as colorectal cell-derived growth factor, ENSG00000109321), betacellulin (ENSG00000174808), epigen (ENSG00000182585), epiregulin (ENSG00000124882), heparin-binding EGF-like growth factor (HB-EGF or diphtheria toxin receptor, ENSG00000113070), neuregulins (NRG-1, also known as Neu differentiation factor, acetylcholine receptor-inducing activity, heregulin or glial growth factor, ENSG00000157168; NRG-2, ENSG00000158458; NRG-3, ENSG00000185737 and NRG-4, ENSG00000169752) and transforming growth factor-α (TGFα, ENSG00000163235). These ligands appear to be generated by proteolytic cleavage of cell-surface peptides.

Nomenclature ErbB1 ErbB3 ErbB4
Other names EGF, HER1 HER3 HER4
Ensembl ID ENSG00000146648 ENSG00000065361 ENSG00000178568
Agonist actvity EGF, amphiregulin, betacellulin, epigen, epiregulin, HB-EGF, TGFα NRG-1, NRG-2 Betacellulin, epiregulin, HB-EGF, NRG-1, NRG-2, NRG-3, NRG-4
Probes [125I]-EGF

The extracellular domain of ErbB2 can be targeted 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, Gaul et al., 2003), gefitinib, erlotinib and tyrphostins AG879 and AG1478.

Abbreviations: Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine, also known as OSI774; gefitinib, N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine, also known as ZD1839; GW583340, N-(3-chloro-4-[{3-fluorophenyl}methoxy]phenyl)-6-(2-[{(2-[methyl-sulfonyl]ethyl)amino}methyl]-4-thiazolyl)-4-quinazolinamine dihydrochloride; tyrphostin AG1478, N-(3-chlorophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride; tyrphostin AG879, α-cyano-(3,5-di-t-butyl-4-hydroxy)thiocinnamide

Further Reading:

BEREZOV, A., GREENE, M.I. & MURALI, R. (2003). Structure-based approaches to inhibition of erbB receptors with peptide mimetics. Immunol. Res., 27, 303–308.

BLACK, J.D., BRATTAIN, M.G., KRISHNAMURTHI, S.A., DAWSON, D.M. & WILLSON, J.K. (2003). ErbB family targeting. Curr. Opin. Investig. Drugs, 4, 1451–1454.

DE BONO, J.S. & ROWINSKY, E.K. (2002). The ErbB receptor family: a therapeutic target for cancer. Trends Mol. Med., 8, S19–S26.

HOLBRO, T., CIVENNI, G. & HYNES, N.E. (2003). The ErbB receptors and their role in cancer progression. Exp. Cell Res., 284, 99–110.

HYNES, N.E. & LANE, H.A. (2005). ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer, 5, 341–354.

NORMANNO, N., BIANCO, C., STRIZZI, L., MANCINO, M., MAIELLO, M.R., DE, L.A., CAPONIGRO, F. & SALOMON, D.S. (2005). The ErbB receptors and their ligands in cancer: an overview. Curr. Drug Targets, 6, 243–257.

ROSKOSKI, R. (2004). The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem. Biophys. Res. Commun., 319, 1–11.

SCHMIDT-ULLRICH, R.K., CONTESSA, J.N., LAMMERING, G., AMORINO, G. & LIN, P.S. (2003). ERBB receptor tyrosine kinases and cellular radiation responses. Oncogene, 22, 5855–5865.

YARDEN, Y. & SLIWKOWSKI, M.X. (2001). Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol., 2, 127–137.


GAUL, M.D. et al. (2003). Bioorg. Med. Chem. Lett., 13, 637–640.

GRAUS-PORTA, D. et al. (1997). EMBO J., 16, 1647–1655.

GDNF family

Overview: GDNF family receptors (provisional nomenclature, ENSF00000001137) are glycosylphosphatidylinositol-linked cell-surface receptors, which, when activated by members of the glial cell-derived neurotrophic factor (GDNF) family, activate a transmembrane tyrosine kinase enzyme, Ret (ENSG00000165731). The endogenous ligands are typically dimeric, linked through disulphide bridges: glial cell line-derived neurotrophic factor (GDNF; 211 aa, ENSG00000168621); neurturin (197 aa, ENSG00000171119); artemin (237 aa, ENSG00000117407) and persephin (156 aa, ENSG00000125650).

Nomenclature GFRα1 GFRα2 GFRα3 GFRα4
Other names GDNF, GNDF family receptor α1 Neurturin, GNDF family receptor α2 Artemin, GNDF family receptor α3 Persephin, GNDF family receptor α4
Ensembl ID ENSG00000151892 ENSG00000168546 ENSG00000146013 ENSG00000125861
Potency order GDNF > neurturin > artemin Neurturin > GDNF Artemin Persephin
Probes [125I]-GDNF (3–63 pm, Treanor et al., 1996; Klein et al., 1997)

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:

AIRAKSINEN, M.S. & SAARMA, M. (2002). The GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci., 3, 383–394.

BALOH, R.H., ENOMOTO, H., JOHNSON, E.M. & MILBRANDT, J. (2000). The GDNF family ligands and receptors — implications for neural development. Curr. Opin. Neurobiol., 10, 103–110.

HARVEY, B.K., HOFFER, B.J. & WANG, Y. (2005). Stroke and TGF-β proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol. Ther., 105, 113–125.

SAARMA, M. (2000). GDNF — a stranger in the TGF-β superfamily? Eur. J. Biochem., 267, 6968–6971.


KLEIN, R.D. et al. (1997). Nature, 387, 717–721.

TREANOR, J.J.S. et al. (1996). Nature, 382, 80–83.

Natriuretic peptide

Overview: Natriuretic peptide receptors (provisional nomenclature) are homodimeric, catalytic receptors with a single TM domain and guanylyl cyclase (EC activity on the intracellular domain of the protein sequence. Isoforms are activated by the peptide hormones α-atrial natriuretic peptide (ANP, ENSG00000175206), brain natriuretic peptide (BNP, ENSG00000120937) and type C-natriuretic peptide (CNP, ENSG00000163273). Another family member is the receptor for guanylin (ENSG00000113389) and uroguanylin (ENSG00000044012). Family members have conserved catalytic and regulatory domains, but divergent ligand-binding domains. The NPR3 receptor has an extracellular binding domain homologous to that of the NPR1 and 2 receptors, 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 & Makhlouf, 1999; Ahluwalia & Hobbs, 2005); NPR3 also binds and removes natriuretic peptides from the circulation, and consequently is often termed the ‘clearance receptor’.

Nomenclature NPR1 NPR2 NPR3 STaR
Other names GC-A, ANPA receptor, NPR-A GC-B, ANPB receptor, NPR-B ANPC receptor, NPR-C, clearance receptor GC-C, guanylin receptor
Ensembl ID ENSG00000169418 ENSG00000159899 ENSG00000113389 ENSG00000070019
Potency order ANP ≥ BNP ≫ CNP CNP ≫ ANP ≥ BNP ANP > CNP > BNP Uroguanylin > guanylin
Selective agonists ANP, BNP, sANP (Olson et al., 1996) CNP cANF4–23 (Maack et al., 1987) E. coli heat-stable enterotoxin (STa)
Selective antagonists A71915 (9.2–9.5, Delporte et al., 1991), [Asu7,23′]-β-ANP7–28 (7.5, Kambayashi et al., 1989), anantin (Wyss et al., 1991) Monoclonal antibody 3G12 (Drewett et al., 1995) AP811 (9.3, Veale et al., 2000), M372049 (Hobbs et al., 2004)
Probes [125I]-ANP [125I]-CNP [125I]-ANP

The polysaccharide obtained from fermentation of Aureobasidium species, HS142–1, acts as an antagonist for NPR1 and NPR2 receptors (Morishita et al., 1991). Orphan receptors GC-D, GC-E (RetGC-1, ENSG00000132518), GC-F (RetGC-2, ENSG00000101890) and GC-G (ENSG00000080218) have been cloned from various mammals. GC-G exhibits structural similarity to the natriuretic peptide receptors (Schulz et al., 1998).

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)-1-arginyl-1-isoleucyl-1-α-aspartyl-N-(2-methylbutyl)-1-argininamide; [Asu7,23′]-β-ANP(7–28), an antiparallel dimer linked by 7-23′and 7′-23 disulphide bonds (Asu, 1-α-aminosuberic acid); cANF4–23, des[Gln18,Ser19,Gly20,Leu21,Gly22]ANP4–23-NH2; HS142-1, Aureobasidium-derived polysaccharide; M372049, (structure not known); sANP, [G9T, R11S, G16R]ANP

Further Reading:

ABASSI, Z., KARRAM, T., ELLAHAM, S., WINAVER, J. & HOFFMAN, A. (2004). Implications of the natriuretic peptide system in the pathogenesis of heart failure: diagnostic and therapeutic importance. Pharmacol. Ther., 102, 223–241.

AHLUWALIA, A. & HOBBS, A.J. (2005). Endothelium-derived C-type natriuretic peptide: more than just a hyperpolarizing factor. Trends Pharmacol. Sci., 26, 162–167.

DOUST, J.A., PIETRZAK, E., DOBSON, A. & GLASZIOU, P. (2005). How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. Br. Med. J., 330, 625.

D'SOUZA, S.P., DAVIS, M. & BAXTER, G.F. (2004). Autocrine and paracrine actions of natriuretic peptides in the heart. Pharmacol. Ther., 101, 113–129.

LUCAS, K.A., PITARI, G.M., KAZEROUNIAN, S., RUIZ-STEWART, I., PARK, J., SCHULZ, S., CHEPENIK, K.P. & WALDMAN, S.A. (2000). Guanylyl cyclases and signaling by cyclic GMP. Pharmacol. Rev., 52, 375–414.

POTTER, L.R. & HUNTER, T. (2001). Guanylyl cyclase-linked natriuretic peptide receptors: structure and regulation. J. Biol. Chem., 276, 6057–6060.

RADEMAKER, M.T. & RICHARDS, A.M. (2005). Cardiac natriuretic peptides for cardiac health. Clin. Sci., 108, 23–36.

SCOTLAND, R.S., AHLUWALIA, A. & HOBBS, A.J. (2005). C-type natriuretic peptide in vascular physiology and disease. Pharmacol. Ther., 105, 85–93.

SILBERBACH, M. & ROBERTS, C.T. (2001). Natriuretic peptide signalling: molecular and cellular pathways to growth regulation. Cell. Signal., 13, 221–231.


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MURTHY, K.S. & MAKHLOUF, G.M. (1999). J. Biol. Chem., 274, 17587–17592.

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Overview: The trk neurotrophin receptors (provisional nomenclature) exhibit a single TM domain, with an intracellular tyrosine kinase catalytic domain (E.C., although various isoforms exist, including truncated forms of trkB and trkC, which lack catalytic domains. The endogenous ligands are small proteins (ca. 120 aa) and include nerve growth factor (NGF, ENSG00000134259), neurotrophin (NT) 3 (ENSG00000185652), NT4/5 (ENSG00000167744) and brain-derived neurotrophic factor (BDNF, ENSG00000176697). p75, which has homologies with the tumour necrosis factor receptor, 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 trkA trkB trkC p75
Other names gp140trk, high-affinity, slow-dissociating NGF receptor gp145trkB gp145trkC p75NTR, low-affinity neurotrophin receptor, NGFR
Ensembl ID ENSG00000117029 ENSG00000148053 ENSG00000140538 ENSG00000064300
Potency order NGF > NT3 BDNF, NT4/5 > NT3 NT3 NGF, BDNF, NT3, NT4/5
Probes [125I]-NGF [125I]-BDNF

An additional related receptor, termed trk3 (ENSG00000162733), has been identified. The selectivity of small molecule peptide mimetics of NGF has not been ascertained (Massa et al., 2003). There are, as yet, no selective antagonists, but activation can be blocked using anti-neurotrophin antisera or selective immunoadhesins that sequester neurotrophins (Shelton et al., 1995). p75 influences the binding of NGF and NT3 to trkA. The ligand selectivity of p75 appears to be dependent on the cell type; for example, in sympathetic neurones, it binds NT3 with comparable affinity to trkC (Dechant et al., 1997).

The intracellular tyrosine kinase activity of the trkA receptor can be inhibited by GW441756 (8.7, Wood et al., 2004) and tyrphostin AG879 (Ohmichi et al., 1993).

Abbreviations: BDNF, brain-derived neurotrophic factor; GW441756, 1,3-dihydro-3-[(1-methyl-1H-indol-3-yl)methylene]-2H-pyrrolo[3,2-b]pyridin-2-one hydrochloride; NGF, nerve growth factor; tyrphostin AG879, α-cyano-(3,5-di-t-butyl-4-hydroxy)thiocinnamide

Further Reading:

BARKER, P.A., HUSSAIN, N.K. & MCPHERSON, P.S. (2002). Retrograde signaling by the neurotrophins follows a well-worn trk. Trends Neurosci., 25, 379–381.

CHAO, M.V. (2003). Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat. Rev. Neurosci., 4, 299–309.

CHAO, M.V. & BOTHWELL, M. (2002). Neurotrophins: to cleave or not to cleave. Neuron, 33, 9–12.

DECHANT, G. & BARDE, Y.A. (2002). The neurotrophin receptor p75NTR: novel functions and implications for diseases of the nervous system. Nat. Neurosci., 5, 1131–1136.

DIJKHUIZEN, P.A. & GHOSH, A. (2005). Regulation of dendritic growth by calcium and neurotrophin signaling. Prog. Brain Res., 147, 17–27.

GINTY, D.D. & SEGAL, R.A. (2002). Retrograde neurotrophin signaling: Trk-ing along the axon. Curr. Opin. Neurobiol., 12, 268–274.

HEERSSEN, H.M. & SEGAL, R.A. (2002). Location, location, location: a spatial view of neurotrophin signal transduction. Trends Neurosci., 25, 160–165.

HEMPSTEAD, B.L. (2002). The many faces of p75NTR. Curr. Opin. Neurobiol., 12, 260–267.

HOWE, C.L. & MOBLEY, W.C. (2005). Long-distance retrograde neurotrophic signaling. Curr. Opin. Neurobiol., 15, 40–48.

HUANG, E.J. & REICHARDT, L.F. (2003). TRK receptors: roles in neuronal signal transduction. Annu. Rev. Biochem., 72, 609–642.

IBANEZ, C.F. (2002). Jekyll-Hyde neurotrophins: the story of proNGF. Trends Neurosci., 25, 284–286.

KALB, R. (2005). The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends Neurosci., 28, 5–11.

MAMIDIPUDI, V. & WOOTEN, M.W. (2002). Dual role for p75NTR signaling in survival and cell death: can intracellular mediators provide an explanation? J. Neurosci. Res., 68, 373–384.

NYKJAER, A., WILLNOW, T.E. & PETERSEN, C.M. (2005). p75NTR — live or let die. Curr. Opin. Neurobiol., 15, 49–57.

ROUX, P.P. & BARKER, P.A. (2002). Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol., 67, 203–233.

SCHARFMAN, H.E. & MACLUSKY, N.J. (2005). Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue? Trends Neurosci, 28, 79–85.

SEGAL, R.A. (2003). Selectivity in neurotrophin signaling: theme and variations. Annu. Rev. Neurosci., 26, 299–330.


DECHANT, G. et al. (1997). J. Neurosci., 17, 5281–5287.

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OHMICHI, M. et al. (1993). Biochemistry, 32, 4650–4658.

SHELTON, D.L. et al. (1995). J. Neurosci., 15, 477–491.

WOOD, E.R. et al. (2004). Bioorg. Med. Chem. Lett., 14, 953–957.

Toll-like family

Overview: Toll-like receptors are single TM cell-surface proteins with multiple leucine-rich regions in the extracellular portion, which participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular protein kinases and regulation of gene transcription. 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 (Ohashi et al., 2000).

Nomenclature TLR2 TLR3 TLR4 TLR5
Other names CD282 CD283 CD284
Ensembl ID ENSG00000137462 ENSG00000164342 ENSG00000136869 ENSG00000187554
Selective agonists Peptidoglycan (Schwandner et al., 1999; Yoshimura et al., 1999) PolyIC (Alexopoulou et al., 2001) LPS (Poltorak et al., 1998), taxol (Kawasaki et al., 2000) Flagellin (Hayashi et al., 2001)

Nomenclature TLR7 TLR8 TLR9
Other names CD289
Ensembl ID ENSG00000196664 ENSG00000101916 ENSG00000173366
Selective agonists R848 (Hemmi et al., 2002), imiquimod (Hemmi et al., 2002) R848 (Hemmi et al., 2002), imiquimod CpG (Hemmi et al., 2000)

Members of the family appear to interact in the recognition of many ligands such that the potency of ligands is altered with different combination patterns (e.g. TLR1/2 and TLR2/6, Takeuchi et al., 2001; 2002).

Further members of the family, which includes TLR1 (Toll/interleukin-1 receptor-like protein, CD281, ENSG00000174125), TLR6 (ENSG00000174130), TLR10 (ENSG00000174123) and TLR11 (ENSMUSG00000051969), have been less well characterised.

Abbreviations: CpG, DNA enriched in cytosine:guanosine pairs; imiquimod, 1-(4-amino-imidazo[4,5-c]quinolin-1-yl)-2-methylpropane, also known as R837; LPS, lipopolysaccharide derived from Gram-negative bacteria; polyIC, polyinosine-polycytosine; R848, 1-(4-amino-2-ethoxymethyl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol, also known as resiquimod and S28463

Further Reading:

AKIRA, S. & TAKEDA, K. (2004). Toll-like receptor signalling. Nat. Rev. Immunol., 4, 499–511.

AKIRA, S. (2003). Toll-like receptor signaling. J. Biol. Chem., 278, 38105–38108.

BASU, S. & FENTON, M.J. (2004). Toll-like receptors: function and roles in lung disease. Am. J. Physiol. Lung Cell Mol. Physiol., 286, L887–L892.

BELL, J.K., MULLEN, G.E., LEIFER, C.A., MAZZONI, A., DAVIES, D.R. & SEGAL, D.M. (2003). Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol., 24, 528–533.

BEUTLER, B. (2000). Tlr4: central component of the sole mammalian LPS sensor. Curr. Opin. Immunol., 12, 20–26.

DE KLEIJN, D. & PASTERKAMP, G. (2003). Toll-like receptors in cardiovascular diseases. Cardiovasc. Res., 60, 58–67.

DUNNE, A. & O'NEILL, L.A. (2005). Adaptor usage and Toll-like receptor signaling specificity. FEBS Lett., 579, 3330–3335.

FUKAO, T. & KOYASU, S. (2003). PI3K and negative regulation of TLR signaling. Trends Immunol., 24, 358–363.

GUERAU-DE-ARELLANO, M. & HUBER, B.T. (2005). Chemokines and Toll-like receptors in Lyme disease pathogenesis. Trends Mol. Med., 11, 114–120.

HERTZOG, P.J., O'NEILL, L.A. & HAMILTON, J.A. (2003). The interferon in TLR signaling: more than just antiviral. Trends Immunol., 24, 534–539.

JENNER, R.G. & YOUNG, R.A. (2005). Insights into host responses against pathogens from transcriptional profiling. Nat. Rev. Microbiol., 3, 281–294.

JOHNSON, G.B., BRUNN, G.J. & PLATT, J.L. (2003). Activation of mammalian Toll-like receptors by endogenous agonists. Crit. Rev. Immunol., 23, 15–44.

KU, C.L., YANG, K., BUSTAMANTE, J., PUEL, A., VON, B.H., SANTOS, O.F., LAWRENCE, T., CHANG, H.H., AL-MOUSA, H., PICARD, C. & CASANOVA, J.L. (2005). Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol. Rev., 203, 10–20.

LIEW, F.Y., XU, D., BRINT, E.K. & O'NEILL, L.A. (2005). Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol., 5, 446–458.

LIU, Y.J. (2005). IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol., 23, 275–306.

MILLER, S.I., ERNST, R.K. & BADER, M.W. (2005). LPS, TLR4 and infectious disease diversity. Nat. Rev. Microbiol., 3, 36–46.

O'NEILL, L.A. (2003). Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. Curr. Opin. Pharmacol., 3, 396–403.

PALSSON-MCDERMOTT, E.M. & O'NEILL, L.A. (2004). Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology, 113, 153–162.

TAKEDA, K., KAISHO, T. & AKIRA, S. (2003). Toll-like receptors. Annu. Rev. Immunol., 21, 335–376.

TSAN, M.F. & GAO, B. (2004). Endogenous ligands of Toll-like receptors. J. Leukoc. Biol., 76, 514–519.


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