BJP7 v. 170

S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors.
British Journal of Pharmacology (2013) 170, 16761705
THE CONCISE GUIDE TO PHARMACOLOGY 2013/14:

CATALYTIC RECEPTORS
Stephen P.H. Alexander*1, Helen E. Benson2, Elena Faccenda2, Adam J. Pawson2,
2
Joanna L. Sharman , Michael Spedding3, John A. Peters4, Anthony J. Harmar2 and
CGTP Collaborators
IUPHAR
International Union of Basic
and Clinical Pharmacology
*Author for correspondence; [email protected]

1
School of Life Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, UK
2
The University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK
3
Spedding Research Solutions SARL, Le Vsinet 78110, France
4
Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
L
N
Abstract
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.
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
Searchable database: http://www.guidetopharmacology.org/index.jsp

Full Contents of Concise Guide: http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full
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- and BMP receptors, has intrinsic
serine/threonine protein kinase activity in the heterodimeric
functional unit. A fifth group is the receptor tyrosine phosphatases (RTP), which 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.
Catalytic receptors 1676
S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors. British Journal of Pharmacology (2013) 170, 16761705
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
1684
1685
1688
1689
1692
1695
1702
1703
Cytokine receptor family

GDNF receptor family
Integrins
Natriuretic peptide receptor family
Pattern Recognition receptors
Receptor serine/threonine kinase (RSTK) family
Receptor tyrosine kinases
Receptor tyrosine phosphatases (RTP)
Tumour necrosis factor (TNF) receptor family

Catalytic receptors 1677
Cytokine receptor family

thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo- or heterodimeric STATs function principally as transcription factors in the
nucleus.
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 heterooligomerisation, 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
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- 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-
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 chain (c): 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
Subunits
Interleukin-2 receptor subunit

(Ligand-binding subunit),
(Other subunit)
Interleukin 4 receptor
(Other subunit)
Interleukin 13 receptor, 1
(Other subunit)
(Other 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]

Cytokine receptor family 1678
Nomenclature
Interleukin 13 receptor, 2
HGNC, UniProt
IL13RA2, Q14627
Subunits

(Ligand-binding subunit), Interleukin 15
receptor, subunit (Ligand-binding subunit),
Interleukin-2 receptor subunit (Other subunit)
Interleukin 21 receptor (Ligand-binding

subunit), Interleukin-2 receptor 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.
Thymic stromal lymphopoietin receptor

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

receptor
Subunits
Interleukin 3 receptor, subunit (Ligand-binding subunit),

Cytokine receptor common subunit (Other subunit)
Interleukin 5 receptor, subunit (Ligand-binding subunit),

GM-CSF receptor, subunit (Ligand-binding subunit),

Endogenous agonists
IL-3 (IL3, P08700)
IL-5 (IL5, P05113)
G-CSF (CSF3, P09919), GM-CSF (CSF2, P04141)
YM90709 [2]

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, 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
Ciliary neutrophic factor receptor
Subunits
Interleukin-6 receptor, subunit

(Ligand-binding subunit), Interleukin-6
receptor, subunit (Other subunit)


(Ligand-binding subunit), Oncostatin
M-specific receptor, subunit (Other subunit)
Ciliary neurotrophic factor receptor subunit

(Ligand-binding subunit), Leukemia inhibitory
factor receptor (Other subunit), Interleukin-6
receptor, 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
HGNC, UniProt
LEPR, P48357
Subunits
Leukemia inhibitory factor receptor

Oncostatin M-specific receptor, subunit

Interleukin 27 receptor, alpha (Ligand-binding

subunit), Interleukin-6 receptor, 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)

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, 2 subunit
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 (, and ) and type II () interferons. There are at least 13 different genesencoding IFN-&ALPHA; subunits in a cluster
on human chromosome 9p22: 1 (IFNA1, P01562), 2 (IFNA2, P01563), 4 (IFNA4, P05014), 5 (IFNA5, P01569), 6 (IFNA6, P05013), 7 (IFNA7, P01567), 8 (IFNA8, P32881), 10 (IFNA10, P01566),
13 (IFNA13, P01562), 14 (IFNA14, P01570), 16 (IFNA16, P05015), 17 (IFNA17, P01571) and 21 (IFNA21, P01568).
Nomenclature
Interferon-/ receptor
Interferon- receptor
Subunits
interferon / receptor 1 (Ligand-binding subunit), Interferon / receptor 2 (Other subunit)
Interferon receptor 1 (Ligand-binding subunit),

Interferon receptor 2 (Other subunit)
Endogenous agonists
IFN-10 (IFNA10, P01566), IFN-1/13 (IFNA1, IFNA13, P01562), IFN-14 (IFNA14, P01570), IFN-16
(IFNA16, P05015), IFN-17 (IFNA17, P01571), IFN-2 (IFNA2, P01563), IFN-21 (IFNA21, P01568), IFN-4
(IFNA4, P05014), IFN-5 (IFNA5, P01569), IFN-6 (IFNA6, P05013), IFN-7 (IFNA7, P01567), IFN-8
(IFNA8, P32881), IFN- (IFNB1, P01574), IFN- (IFNK, Q9P0W0), IFN- (IFNW1, P05000)
IFN- (IFNG, P01579)

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-221/20
heteromer
Interleukin-221/10
heteromer
Interleukin-22 receptor 2
Interferon- receptor 1
HGNC, UniProt
IL22RA2, Q969J5
Subunits
Interleukin 10 receptor,
subunit (Ligand-binding
subunit), Interleukin 10
receptor, subunit (Other
subunit)
receptor, subunit (Other
subunit)
receptor, 1 subunit
(Ligand-binding subunit)
receptor, 1 subunit
(Ligand-binding subunit)
Interferon- receptor 1
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-1 (IFNL1, Q8IU54),

IFN-2 (IFNL2, Q8IZJ0),
IFN-3 (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
Interleukin-1 receptor, type I
Interleukin-1 receptor, type II
Subunits
Interleukin 1 receptor, type I

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

(Other subunit)
Interleukin-18 1
(Other subunit)
Endogenous agonists
IL-1 (IL1A, P01583), IL-1

(IL1B, P01584)
IL-33 (IL33, O95760)
IL-36 (IL36A, Q9UHA7), IL-36

(IL36B, Q9NZH7), IL-36 (IL36G,
Q9NZH8),
IL-18 (IL18, Q14116), IL-37

(IL37, Q9NZH6)
Endogenous antagonists
IL-1 receptor antagonist (IL1RN,

P18510)

Q9UBH0)
AF12198 [1]
Comment

Q9UBH0) is a highly specific
antagonist of the response to
IL-36 (IL36G, Q9NZH8)
Decoy receptor that binds IL-1

(IL1A, P01583), IL-1 (IL1B,
P01584) and IL-1 receptor
antagonist (IL1RN, P18510)

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

Interleukin-17 receptor D
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: 277302. [PMID:23046136]
Chang SH, Dong C. (2011) Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 23: 10691075. [PMID:21130872]
Donnelly RP, Dickensheets H, OBrien TR. (2011) Interferon-lambda and therapy for chronic
hepatitis C virus infection. Trends Immunol 32: 443450. [PMID:21820962]
George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. (2012) Pharmacology and therapeutic
potential of interferons. Pharmacol Ther 135: 4453. [PMID:22484806]
Gibbert K, Schlaak JF, Yang D, Dittmer U. (2013) IFN- subtypes: distinct biological activities in
anti-viral therapy. Br J Pharmacol 168: 10481058. [PMID:23072338]
Mackall CL, Fry TJ, Gress RE. (2011) Harnessing the biology of IL-7 for therapeutic application. Nat
Rev Immunol 11: 330342. [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: 143159. [PMID:22029668]
Miller AM, Liew FY. (2011) The IL-33/ST2 pathwayA new therapeutic target in cardiovascular
disease. Pharmacol Ther 131: 179186. [PMID:21356240]
Miossec P, Kolls JK. (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug
Discov 11: 763776. [PMID:23023676]
Murugaiyan G, Saha B. (2013) IL-27 in tumor immunity and immunotherapy. Trends Mol Med 19:
108116. [PMID:23306374]
Palmer G, Gabay C. (2011) Interleukin-33 biology with potential insights into human diseases. Nat
Rev Rheumatol 7: 321329. [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: 816.
[PMID:21726218]
Pappu R, Rutz S, Ouyang W. (2012) Regulation of epithelial immunity by IL-17 family cytokines.
Trends Immunol 33: 343349. [PMID:22476048]

Parker D, Prince A. (2011) Type I interferon response to extracellular bacteria in the airway
epithelium. Trends Immunol 32: 582588. [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: 929979. [PMID:15032600]
Rincon M. (2012) Interleukin-6: from an inflammatory marker to a target for inflammatory diseases.
Trends Immunol 33: 571577. [PMID:22883707]
Rubino SJ, Geddes K, Girardin SE. (2012) Innate IL-17 and IL-22 responses to enteric bacterial
pathogens. Trends Immunol 33: 112118. [PMID:22342740]
Sato N, Miyajima A. (1994) Multimeric cytokine receptors: common versus specific functions. Curr
Opin Cell Biol 6: 174179. [PMID:8024807]
Schindler C, Levy DE, Decker T. (2007) JAK-STAT signaling: from interferons to cytokines. J Biol
Chem 282: 2005920063. [PMID:17502367]
Shevach EM. (2012) Application of IL-2 therapy to target T regulatory cell function. Trends Immunol
33: 626632. [PMID:22951308]
Steel JC, Waldmann TA, Morris JC. (2012) Interleukin-15 biology and its therapeutic implications in
cancer. Trends Pharmacol Sci 33: 3541. [PMID:22032984]
Tanaka T, Narazaki M, Kishimoto T. (2012) Therapeutic targeting of the interleukin-6 receptor. Annu
Rev Pharmacol Toxicol 52: 199219. [PMID:21910626]
van der Lely AJ, Kopchick JJ. (2006) Growth hormone receptor antagonists. Neuroendocrinology 83:
264268. [PMID:17047392]
Wojno ED, Hunter CA. (2012) New directions in the basic and translational biology of interleukin27. Trends Immunol 33: 9197. [PMID:22177689]
Zepp J, Wu L, Li X. (2011) IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Trends Immunol 32: 232239. [PMID:21493143]
Zhu S, Qian Y. (2012) IL-17/IL-17 receptor system in autoimmune disease: mechanisms and
therapeutic potential. Clin Sci 122: 487511. [PMID:22324470]
GDNF receptor family

Overview: GDNF family receptors (provisional nomenclature)
are extrinsic tyrosine kinase receptors. Ligand binding to the
extracellular domain of the glycosylphosphatidylinositollinked 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, O60542) (PSPN, 156 aa).
Nomenclature
GDNF family receptor 1
Common abbreviation
GFR1
GFR2
GFR3

GFR4
HGNC, UniProt
GFRA1, P56159
GFRA2, O00451
GFRA3, O60609
GFRA4, Q9GZZ7
Potency order
GDNF (GDNF, P39905) > NRTN (NRTN, Q99748)

> ARTN (ARTN, Q5T4W7)
NRTN (NRTN, Q99748) > GDNF (GDNF, P39905)
ARTN (ARTN, Q5T4W7)
PSPN (PSPN, O60542)
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 Hirschsprungs 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: 155175. [PMID:23348013]
Carnicella S, Ron D. (2009) GDNFa potential target to treat addiction. Pharmacol Ther 122: 918.
[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: 112120. [PMID:22503821]

Mickiewicz AL, Kordower JH. (2011) GDNF family ligands: a potential future for Parkinsons disease
therapy. CNS Neurol Disord Drug Targets 10: 703711. [PMID:21838676]
Pascual A, Hidalgo-Figueroa M, Gmez-Daz R, Lpez-Barneo J. (2011) GDNF and protection of adult
central catecholaminergic neurons. J Mol Endocrinol 46: R83R92. [PMID:21357726]
Rangasamy SB, Soderstrom K, Bakay RA, Kordower JH. (2010) Neurotrophic factor therapy for
Parkinsons disease. Prog Brain Res 184: 237264. [PMID:20887879]
GDNF receptor family 1684
Integrins
Overview: Integrins (provisional nomenclature) are heterodimeric entities, composed of and 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 subunit, and if present
(in 1, 2, 10, 11, D, E, L, M and X), this I domain
contains the ligand binding site. All subunits possess a similar
I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an subunit I domain
precludes ligand binding through the 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 (pIC50)
Comment
11
integrin, alpha 1 subunit, integrin, beta 1 subunit (fibronectin

receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)
collagen, laminin
obtustatin (9.1) [11]
21
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]
IIb3
integrin, alpha 2b subunit (platelet glycoprotein IIb 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
41
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
L2
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]
V3
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]

Integrins 1685
Subunits
Nomenclature
HGNC, UniProt
integrin, alpha 1 subunit
ITGA1, P56199
integrin, alpha 2 subunit (CD49B, alpha 2 subunit of VLA-2 receptor)
ITGA2, P08514
integrin, alpha 2b subunit (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41)
ITGA2B, P17301
integrin, alpha 3 subunit (antigen CD49C, alpha 3 subunit of VLA-3 receptor)
ITGA3, P26006
integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA-4 receptor)
ITGA4, P13612
integrin, alpha 5 subunit (fibronectin receptor, alpha polypeptide)
ITGA5, P08648
ITGA6, P23229
ITGA7, Q13683
ITGA8, P53708
ITGA9, Q13797
ITGA10, O75578
ITGA11, Q9UKX5
integrin, alpha D subunit
ITGAD, Q13349
integrin, alpha E subunit (antigen CD103, human mucosal lymphocyte antigen 1; alpha polypeptide)
ITGAE, P38570
integrin, alpha L subunit (antigen CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide)
ITGAL, P20701
integrin, alpha M subunit (complement component 3 receptor 3 subunit)
ITGAM, P11215
integrin, alpha V subunit
ITGAV, P06756
integrin, 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
ITGB5, P18084
ITGB6, P18564
ITGB7, P26010
ITGB8, P26012

Integrins 1686
Integrin ligands Collagen is the most abundant protein in

metazoa, rich in glycine and proline residues, made up of crosslinked triple helical structures, generated primarily by fibroblasts. Extensive post-translational processing is conducted by
prolyl and lysyl hydroxylases, as well as transglutaminases. Over
40 genes for collagen- subunits have been identified in the
human genome. The collagen-binding integrins 11, 21,
101 and 111 recognise a range of triple-helical peptide
motifs including GFOGER (O = hydroxyproline), a synthetic
peptide.
Laminin is an extracellular glycoprotein composed of , and
chains, for which five, four and three genes, respectively, are
identified in the human genome. It binds to 11, 21, 3,1,
71 and 64 integrins10.
Fibrinogen is a glycosylated hexamer composed of two (FGA,

P02671), two (FGB, P02675) and two (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 IIb3; proteolysis by
thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation
cascade.
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.
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.
Von Willebrand factor (VWF, P04275) is a glycoprotein synthesised in vascular endothelial cells as a disulphide-linked homodimer, but multimerises further in plasma and is deposited on
vessel wall collagen as a high molecular weight multimer. It is
responsible for capturing platelets under arterial shear flow (via
GPIb) and in thrombus propagation (via integrin IIb3).
Osteopontin forms an integral part of the mineralized matrix

in bone (SPP1, P10451), where it undergoes extensive
post-translation
processing,
including
proteolysis
and
phosphorylation.
Further reading
Anthis NJ, Campbell ID. (2011) The tail of integrin activation. Trends Biochem Sci 36: 191198.
[PMID:21216149]
Bledzka K, Smyth SS, Plow EF. (2013) Integrin IIb3: from discovery to efficacious therapeutic
target. Circ Res 112: 11891200. [PMID:23580774]
Cavallaro U, Dejana E. (2011) Adhesion molecule signalling: not always a sticky business. Nat Rev
Mol Cell Biol 12: 189197. [PMID:21346732]
Cox D, Brennan M, Moran N. (2010) Integrins as therapeutic targets: lessons and opportunities. Nat
Rev Drug Discov 9: 804820. [PMID:20885411]
Hogg N, Patzak I, Willenbrock F. (2011) The insiders guide to leukocyte integrin signalling and
function. Nat Rev Immunol 11: 416426. [PMID:21597477]
Hu P, Luo BH. (2013) Integrin bi-directional signaling across the plasma membrane. J Cell Physiol
228: 306312. [PMID:22767296]
Humphries JD, Byron A, Humphries MJ. (2006) Integrin ligands at a glance. J Cell Sci 119 (Pt 19):
39013903. [PMID:16988024]

Ivaska J, Heino J. (2011) Cooperation between integrins and growth factor receptors in signaling
and endocytosis. Annu Rev Cell Dev Biol 27: 291320. [PMID:21663443]
Kim C, Ye F, Ginsberg MH. (2011) Regulation of integrin activation. Annu Rev Cell Dev Biol 27:
321345. [PMID:21663444]
Roca-Cusachs P, Iskratsch T, Sheetz MP. (2012) Finding the weakest link: exploring integrinmediated mechanical molecular pathways. J Cell Sci 125 (Pt 13): 30253038. [PMID:22797926]
Shattil SJ, Kim C, Ginsberg MH. (2010) The final steps of integrin activation: the end game. Nat Rev
Mol Cell Biol 11: 288300. [PMID:20308986]
Weber GF, Bjerke MA, DeSimone DW. (2011) Integrins and cadherins join forces to form adhesive
networks. J Cell Sci 124 (Pt 8): 11831193. [PMID:21444749]
Wickstrm SA, Fssler R. (2011) Regulation of membrane traffic by integrin signaling. Trends Cell
Biol 21: 266273. [PMID:21440440]
Wu X, Reddy DS. (2012) Integrins as receptor targets for neurological disorders. Pharmacol Ther 134:
6881. [PMID:22233753]
Integrins 1687
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,
Nomenclature
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
NPR-A
NPR-B
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].
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]
anantin [29], A-71915 (pKi 9.2 9.5) [15],

[Asu7,23]-ANP-(7-28) (pKi 7.5) [21]
monoclonal antibody 3G12 [17],

[Ser11](N-CNP,C-ANP)pBNP2-15 [16]
M372049 [19], AP811 (pKi 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 (RetGC1, 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:
522531. [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:
18181829. [PMID:21375693]
Pandey KN. (2011) The functional genomics of guanylyl cyclase/natriuretic peptide receptor-A:
perspectives and paradigms. FEBS J 278: 17921807. [PMID:21375691]

Potter LR. (2011) Guanylyl cyclase structure, function and regulation. Cell Signal 23: 19211926.
[PMID:21914472]
Potter LR. (2011) Natriuretic peptide metabolism, clearance and degradation. FEBS J 278:
18081817. [PMID:21375692]
Potter LR. (2011) Regulation and therapeutic targeting of peptide-activated receptor guanylyl
cyclases. Pharmacol Ther 130: 7182. [PMID:21185863]
Natriuretic peptide receptor family 1688
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 pathogenassociated molecular patterns, which includes peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and
nucleic acids.
ligand binding substantially (e.g. TLR1/2 and TLR2/6, [4344]).

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].
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
Nomenclature
HGNC, UniProt
Agonists
Comment
TLR1
TLR1, Q15399
TLR2
TLR2, O60603
peptidoglycan [41,45]
TLR3
TLR3, O15455
polyIC [30]
TLR4
TLR4, O00206
LPS [39], taxol [36]
eritoran (E5564) is a lipid A analogue, which has been described as a TLR4 antagonist [35]
TLR5
TLR5, O60602
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 NFB 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.
Pattern Recognition receptors 1689
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 (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: 535542. [PMID:19556980]
Buchanan MM, Hutchinson M, Watkins LR, Yin H. (2010) Toll-like receptor 4 in CNS pathologies.
J Neurochem 114: 1327. [PMID:20402965]
Celis E. (2007) Toll-like receptor ligands energize peptide vaccines through multiple paths. Cancer
Res 67: 79457947. [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: H112. [PMID:19011041]
Chiron D, Jego G, Pellat-Deuceunynck C. (2010) Toll-like receptors: expression and involvement in
multiple myeloma. Leuk Res 34: 15451550. [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: 18721888. [PMID:20649586]
Ehlers M, Ravetch JV. (2007) Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol 28: 7479. [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: 343359. [PMID:17845139]
Hennessy EJ, Parker AE, ONeill LA. (2010) Targeting Toll-like receptors: emerging therapeutics?. Nat
Rev Drug Discov 9: 293307. [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: 391397.
[PMID:20832362]
Hori M, Nishida K. (2008) Toll-like receptor signaling: defensive or offensive for the heart?. Circ Res
102: 137139. [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: 552559. [PMID:17479101]
Knner AC, Brning JC. (2011) Toll-like receptors: linking inflammation to metabolism. Trends
Endocrinol Metab 22: 1623. [PMID:20888253]
Lecat A, Piette J, Legrand-Poels S. (2010) The protein Nod2: an innate receptor more complex than
previously assumed. Biochem Pharmacol 80: 20212031. [PMID:20643110]
Li H, Sun B. (2007) Toll-like receptor 4 in atherosclerosis. J Cell Mol Med 11: 8895. [PMID:17367503]
Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP. (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158: 10071020. [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: 419441.
[PMID:17378763]
Monie TP, Bryant CE, Gay NJ. (2009) Activating immunity: lessons from the TLRs and NLRs. Trends
Biochem Sci 34: 553561. [PMID:19818630]

ONeill LA, Bowie AG. (2007) The family of five: TIR-domain-containing adaptors in Toll-like
receptor signalling. Nat Rev Immunol 7: 353364. [PMID:17457343]
ONeill LA, Sheedy FJ, McCoy CE. (2011) MicroRNAs: the fine-tuners of Toll-like receptor signalling.
Nat Rev Immunol 11: 163175. [PMID:21331081]
Sabroe I, Parker LC, Dower SK, Whyte MK. (2008) The role of TLR activation in inflammation.
J Pathol 214: 126135. [PMID:18161748]
Saitoh S, Miyake K. (2009) Regulatory molecules required for nucleotide-sensing Toll-like receptors.
Immunol Rev 227: 3243. [PMID:19120473]
Sanjuan MA, Milasta S, Green DR. (2009) Toll-like receptor signaling in the lysosomal pathways.
Immunol Rev 227: 203220. [PMID:19120486]
Schroder K, Tschopp J. (2010) The inflammasomes. Cell 140: 821832. [PMID:20303873]
Shaw PJ, Lamkanfi M, Kanneganti TD. (2010) NOD-like receptor (NLR) signaling beyond the
inflammasome. Eur J Immunol 40: 624627. [PMID:20201016]
Takeuchi O, Akira S. (2010) Pattern recognition receptors and inflammation. Cell 140: 805820.
[PMID:20303872]
Trinchieri G, Sher A. (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat
Rev Immunol 7: 179190. [PMID:17318230]
Wenzel J, Tormo D, Tting T. (2008) Toll-like receptor-agonists in the treatment of skin cancer:
history, current developments and future prospects. Handb Exp Pharmacol (183): 201220.
[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: 124130. [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 (TGF) and bone morphogenetic protein (BMP)
families, and may be divided into two subfamilies on the basis of
structural similarities. Agonist binding initiates formation of a
cell-surface complex of type I and type II RSTK, possibly heterotetrameric, where where both subunits express serine/threonine
kinase activity. The type I receptor serine/threonine kinases
(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. TGF 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
TGF/activin/nodal subfamily and the BMP/GDF (growth/
differentiation factor)/MIS (Mllerian 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 heterodimeric complexes. Thus, inhibins are subunits linked to a
variety of chains, while activins are combinations of 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

II-like 1
activin A receptor,
type I
bone morphogenetic
protein receptor, type IA
activin A receptor,
type IB
transforming growth
factor, beta receptor 1
bone morphogenetic
protein receptor, type IB
activin A receptor,
type IC
Common abbreviation
ALK1
ALK2
BMPR1A
ALK4
TGFBR1
BMPR1B
ALK7
HGNC, UniProt
ACVRL1, P37023
ACVR1, Q04771
BMPR1A, P36894
ACVR1B, P36896
TGFBR1, P36897
BMPR1B, O00238
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

Receptor serine/threonine kinase (RSTK) family 1692
Type III receptor serine/threonine kinases
Nomenclature
transforming growth factor, beta receptor III
Common abbreviation
TGFBR3
HGNC, UniProt
TGFBR3, Q03167
RSTK functional heteromers
Nomenclature
Transforming growth factor

receptor
Bone morphogenetic protein

receptors
Growth/differentiation factor
receptors
Activin receptors
Anti-Mllerian hormone receptors
Subunits
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)
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)

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

receptor, type IA (Type I), bone
type IB (Type I), anti-Mullerian
hormone receptor, type II (Type II)
Coupling
Smad2, Smad3 [4849]
Smad1, Smad5, Smad8 [4849]
Smad2, Smad3 [49]
Endogenous
agonists
TGF1 (TGFB1, P01137), TGF2

(TGFB2, P61812), TGF3 (TGFB3,
P10600)
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)
GDF1 (GDF1, P27539), GDF10

(GDF10, P55107), GDF9 (GDF9,
O60383), GDF3 (GDF3, Q9NR23)
inhibin A (INHBA, P08476),

inhibin B (INHBB, P09529)
Mllerian inhibiting substance

(AMH, P03971)
Comments: A number of endogenous inhibitory ligands have been identified for RSTKs, including BMP3, inhibin, inhibinC and inhibinE.
An appraisal of small molecule inhibitors of TGF and BMP signalling concluded that TGF pathway inhibitors were more selective than BMP signalling inhibitors [50]. The authors confirmed the
selectivity of SB505124 to inhibit TGF 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
Smad6
SMAD6, O43541
HsT17432, MADH6, MADH7
Smad7
SMAD7, O15105
MADH7, MADH8
Smad8
SMAD9, O15198
MADH6, MADH9
Further reading
Ehrlich M, Horbelt D, Marom B, Knaus P, Henis YI. (2011) Homomeric and heteromeric complexes
among TGF- and BMP receptors and their roles in signaling. Cell Signal 23: 14241432.
[PMID:21515362]
Hinck AP. (2012) Structural studies of the TGF-s and their receptors - insights into evolution of the
TGF- superfamily. FEBS Lett 586: 18601870. [PMID:22651914]
Massagu J. (2012) TGF signalling in context. Nat Rev Mol Cell Biol 13: 616630. [PMID:22992590]
Moustakas A, Heldin CH. (2009) The regulation of TGFbeta signal transduction. Development 136:
36993714. [PMID:19855013]

Rider CC, Mulloy B. (2010) Bone morphogenetic protein and growth differentiation factor cytokine
families and their protein antagonists. Biochem J 429: 112. [PMID:20545624]
Santibaez JF, Quintanilla M, Bernabeu C. (2011) TGF-/TGF- receptor system and its role in
physiological and pathological conditions. Clin Sci 121: 233251. [PMID:21615335]
Xu P, Liu J, Derynck R. (2012) Post-translational regulation of TGF- receptor and Smad signaling.
FEBS Lett 586: 18711884. [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 polypeptide and protein hormones, cytokines and growth factors are
key regulators of critical cellular processes, such as proliferation
and differentiation, cell survival and metabolism, cell migration
and cell cycle control [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 transduction pathways, including phospholipase C-, mitogenactivated 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.
ligand [66]. Ligands of the ErbB family of receptors are peptides,

many of which are generated by proteolytic cleavage of cellsurface 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.
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; ERBB2,
P04626) appears to act as an essential partner for the other
members of the family without itself being activated by a cognate
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, O14944), HB-EGF (HBEGF, Q99075), TGF
(TGFA, P01135)
v-erb-b2 avian erythroblastic leukemia

viral oncogene homolog 3
HER3
ERBB3, P21860
NRG-1 (NRG1, Q02297), NRG-2 (NRG2, O14511)
v-erb-b2 avian erythroblastic leukemia

viral oncogene homolog 4
HER4
ERBB4, Q15303
betacellulin (BTC, P35070), epiregulin (EREG, O14944), HB-EGF (HBEGF, Q99075),

NRG-1 (NRG1, Q02297), NRG-2 (NRG2, O14511), 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 (7.98.0, [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).
Receptor tyrosine kinases 1695
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.
PQ401 inhibits the insulin-like growth factor receptor [56], while

BMS-536924 inhibits both the insulin receptor and the insulinlike growth factor receptor [85].
Antibodies targetting IGF1, IGF2 and the extracellular portion of

the IGF1 receptor are in clinical trials.
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

receptor, alpha polypeptide
platelet-derived growth factor

receptor, beta polypeptide
v-kit Hardy-Zuckerman 4 feline

sarcoma viral oncogene homolog
colony stimulating factor 1

receptor
fms-related tyrosine kinase 3
Common abbreviation
PDGFR
PDGFR
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 lymphangiogenesis; 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
kinase insert domain receptor (a type III receptor

tyrosine kinase)
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
fibroblast growth factor receptor 1
Common abbreviation
FGFR1
FGFR2
FGFR3
FGFR4
HGNC, UniProt
FGFR1, P11362
FGFR2, P21802
FGFR3, P22607
FGFR4, P22455
Endogenous ligands
FGF-1 (FGF1, P05230), FGF-2 (FGF2,

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

P09038), FGF-9 (FGF9, P31371) > FGF-4
(FGF4, P08620), FGF-8 (FGF8, P55075)
[77]
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 B (NF-B)
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
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 tyrosine kinase activity of the trkA receptor can be inhibited by
GW441756 (pIC50= 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
receptor tyrosine kinase-like orphan receptor 1
Common abbreviation
ROR1
receptor tyrosine kinase-like orphan receptor 2

ROR2
HGNC, UniProt
ROR1, Q01973
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 heterodimer linked by a disulphide bridge. The maturation of HGF is
enhanced by a serine protease, HGF activating complex, and

inhibited by HGF-inhibitor 1, 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
receptor
A1
EPH
receptor
A2
EPH
receptor
A3
EPH
receptor
A4
EPH
receptor
A5
EPH
receptor
A6
EPH
receptor
A7
EPH
receptor
A8
EPH
receptor
A10
EPH
receptor
B1
EPH
receptor
B2
EPH
receptor
B3
EPH
receptor
B4
EPH
receptor
B6
Common abbreviation
EphA1
EphA2
EphA3
EphA4
EphA5
EphA6
EphA7
EphA8
EphA10
EphB1
EphB2
EphB3
EphB4
EphB6
HGNC, UniProt
EPHA1,
P21709
EPHA2,
P29317
EPHA3,
P29320
EPHA4,
P54764
EPHA5,
P54756
EPHA6,
Q9UF33
EPHA7,
Q15375
EPHA8,
P29322
EPHA10,
Q5JZY3
EPHB1,
P54762
EPHB2,
P29323
EPHB3,
P54753
EPHB4,
P54760
EPHB6,
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 posttranslational 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
discoidin domain receptor tyrosine kinase 1
Common abbreviation
DDR1
discoidin domain receptor tyrosine kinase 2

DDR2
HGNC, UniProt
DDR1, Q08345
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:
652661. [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: 1632.
[PMID:22124364]
Camidge DR, Doebele RC. (2012) Treating ALK-positive lung cancerearly successes and future
challenges. Nat Rev Clin Oncol 9: 268277. [PMID:22473102]
Chen Y, Fu AK, Ip NY. (2012) Eph receptors at synapses: implications in neurodegenerative diseases.
Cell Signal 24: 606611. [PMID:22120527]
Fu HL, Valiathan RR, Arkwright R, Sohail A, Mihai C, Kumarasiri M, Mahasenan KV, Mobashery S,
Huang P, Agarwal G et al. (2013) Discoidin domain receptors: unique receptor tyrosine kinases in
collagen-mediated signaling. J Biol Chem 288: 74307437. [PMID:23335507]
Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. (2012) Targeting MET in cancer: rationale
and progress. Nat Rev Cancer 12: 89103. [PMID:22270953]
Goetz R, Mohammadi M. (2013) Exploring mechanisms of FGF signalling through the lens of
structural biology. Nat Rev Mol Cell Biol 14: 166180. [PMID:23403721]
Guillemot F, Zimmer C. (2011) From cradle to grave: the multiple roles of fibroblast growth factors
in neural development. Neuron 71: 574588. [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: 1522. [PMID:21610047]
Ibez CF, Simi A. (2012) p75 neurotrophin receptor signaling in nervous system injury and
degeneration: paradox and opportunity. Trends Neurosci 35: 431440. [PMID:22503537]
Koh GY. (2013) Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med 19:
3139. [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: 8090. [PMID:21439312]
Lefebvre J, Ancot F, Leroy C, Muharram G, Lemire A, Tulasne D. (2012) Met degradation: more
than one stone to shoot a receptor down. FASEB J 26: 13871399. [PMID:22223753]

Leitinger B. (2011) Transmembrane collagen receptors. Annu Rev Cell Dev Biol 27: 265290.
[PMID:21568710]
Lennartsson J, Rnnstrand L. (2012) Stem cell factor receptor/c-Kit: from basic science to clinical
implications. Physiol Rev 92: 16191649. [PMID:23073628]
Liang G, Liu Z, Wu J, Cai Y, Li X. (2012) Anticancer molecules targeting fibroblast growth factor
receptors. Trends Pharmacol Sci 33: 531541. [PMID:22884522]
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their ligands: promising molecular biomarkers and therapeutic targets in prostate cancer. Biochim
Biophys Acta 1835: 243257. [PMID:23396052]
Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. (2013) BDNF-based synaptic repair as a diseasemodifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14: 401416.
[PMID:23674053]
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Peters S, Adjei AA. (2012) MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol 9:
314326. [PMID:22566105]
Roskoski Jr R. (2013) Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and
pharmacological inhibition. Pharmacol Res 68: 6894. [PMID:23201355]
Sheffler-Collins SI, Dalva MB. (2012) EphBs: an integral link between synaptic function and synaptopathies. Trends Neurosci 35: 293304. [PMID:22516618]
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[PMID:23172303]
Turner CA, Watson SJ, Akil H. (2012) The fibroblast growth factor family: neuromodulation of
affective behavior. Neuron 76: 160174. [PMID:23040813]
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21: 118123. [PMID:22681967]
Yamanashi Y, Tezuka T, Yokoyama K. (2012) Activation of receptor protein-tyrosine kinases from
the cytoplasmic compartment. J Biochem 151: 353359. [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
Bhmer F, Szedlacsek S, Tabernero L, Ostman A, den Hertog J. (2013) Protein tyrosine phosphatase
structure-function relationships in regulation and pathogenesis. FEBS J 280: 413431.
[PMID:22682070]
Dushek O, Goyette J, van der Merwe PA. (2012) Non-catalytic tyrosine-phosphorylated receptors.
Immunol Rev 250: 258276. [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: 731750. [PMID:22816879]

Julien SG, Dub N, Hardy S, Tremblay ML. (2011) Inside the human cancer tyrosine phosphatome.
Nat Rev Cancer 11: 3549. [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: 388400. [PMID:22682003]
Sastry SK, Elferink LA. (2011) Checks and balances: interplay of RTKs and PTPs in cancer progression. Biochem Pharmacol 82: 435440. [PMID:21704606]
Receptor tyrosine phosphatases (RTP) 1702
Tumour necrosis factor (TNF) receptor family

Overview: The TNF receptor superfamily (TNFRSF, provisional
nomenclature) displays limited homology beyond an extracellular domain rich in cysteine residues and is activated by at least 18
different human homologues of TNF referred to as the TNF superfamily (TNFSF). Some homologues lacking transmembrane and
cytoplasmic domains function as decoy receptors binding ligand
without inducing cell signalling. Many of these receptors and
ligands function as multimeric entities. 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 B 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 receptor
TNFRSF3
LTBR, P36941
TRAF3, TRAF4, TRAF5
LIGHT (TNFSF14, O43557), lymphotoxin 21

heterotrimer (LTA, LTB, Q06643, P01374)
OX40
TNFRSF4
TNFRSF4, P43489
TRAF1, TRAF2, TRAF3,

TRAF5
OX-40 ligand (TNFSF4, P23510)
CD40
TNFRSF5
CD40, P25942

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

TRAF5
CD30 ligand (TNFSF8, P32971)
4-1BB
TNFRSF9
TNFRSF9, Q07011
TRAF1, TRAF2, TRAF3
4-1BB ligand (TNFSF9, P41273)
death receptor 4
TNFRSF10A
DR4
TNFRSF10A, O00220
FADD
TRAIL (TNFSF10, P50591)
death receptor 5
TNFRSF10B
DR5
TNFRSF10B, O14763
FADD
receptor activator of
NF-kappa B
TNFRSF11A
RANK
TNFRSF11A, Q9Y6Q6

TRAF5, TRAF6
RANK ligand (TNFSF11, O14788)
osteoprotegerin
TNFRSF11B
OPG
TNFRSF11B, O00300
Acts as a decoy receptor for

RANK ligand (TNFSF11,
O14788) and possibly for
death receptor 3
TNFRSF25
DR3
TNFRSF25, Q93038
TRADD
TL1A (TNFSF15, O95150)
TWEAK receptor
TNFRSF12A
TNFRSF12A, Q9NP84
TRAF1, TRAF2, TRAF3
TWEAK (TNFSF12, O43508)
TACI
TNFRSF13B
TNFRSF13B, O14836
TRAF2, TRAF5, TRAF6
APRIL (TNFSF13, O75888), BAFF (TNFSF13B,

Q9Y275)

Tumour necrosis factor (TNF) receptor family 1703
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

TRAF5, TRAF6
APRIL (TNFSF13, O75888), BAFF (TNFSF13B,

Q9Y275)
glucocorticoid-induced
TNF receptor
TNFRSF18
GITR
TNFRSF18, Q9Y5U5

SIVA
TL6 (TNFSF18, Q9UNG2)
toxicity and JNK inducer
TNFRSF19
TAJ
TNFRSF19, Q9NS68

TRAF5
TNFSF1 (LTA, P01374)
RELT
TNFRSF19L
RELT, Q969Z4
TRAF1
death receptor 6
TNFRSF21
DR6
TNFRSF21, O75509
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 neurotrophins 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: 745756. [PMID:12949498]
Ashkenazi A. (2002) Targeting death and decoy receptors of the tumour-necrosis factor superfamily.
Nat Rev Cancer 2: 420430. [PMID:12189384]
Huang EJ, Reichardt LF. (2001) Neurotrophins: roles in neuronal development and function. Annu
Rev Neurosci 24: 677736. [PMID:11520916]

Mahmood Z, Shukla Y. (2010) Death receptors: targets for cancer therapy. Exp Cell Res 316: 887899.
[PMID:20026107]
Rickert RC, Jellusova J, Miletic AV. (2011) Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 244: 115133. [PMID:22017435]
Tansey MG, Szymkowski DE. (2009) The TNF superfamily in 2009: new pathways, new indications,
and new drugs. Drug Discov Today 14: 10821088. [PMID:19837186]
Tumour necrosis factor (TNF) receptor family 1704
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S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors.

British Journal of Pharmacology (2013) 170, 16761705

THE CONCISE GUIDE TO PHARMACOLOGY 2013/14:

*Author for correspondence; [email protected]

An Introduction to Catalytic Receptors

Amongst the catalytic receptors, particular subfamilies may be

Searchable database: http://www.guidetopharmacology.org/index.jsp

GDNF receptor families, where one, catalytically silent, member

Catalytic receptors 1676

Cytokine receptor family

Searchable database: http://www.guidetopharmacology.org/index.jsp

Catalytic receptors 1677

Cytokine receptor family

globulin (Ig)-like and fibronectin type III (FBNIII)-like domains, a

Overview: Cytokines are not a clearly defined group of agents,

Type I cytokine receptors are characterized by two pairs of

IL-2 receptor family

Interleukin-4 receptor type I

Interleukin-4 receptor type II

Interleukin-2 receptor subunit

IL-2 (IL2, P60568)

IL-4 (IL4, P05112)

IL-13 (IL13, P35225),

IL-7 (IL7, P13232)

IL-9 (IL9, P15248)

IL-1 receptor antagonist

AF12198 [1], Ro264550 [3]

Searchable database: http://www.guidetopharmacology.org/index.jsp

Cytokine receptor family 1678

Interleukin-2 receptor subunit

Interleukin 21 receptor (Ligand-binding

Interleukin 7 receptor (Ligand-binding subunit),

IL-15 (IL15, P40933)

IL-21 (IL21, Q9HBE4)

TSLP (TSLP, Q969D9)

Decoy receptor that binds IL-13

Thymic stromal lymphopoietin receptor

IL-3 receptor family

Granulocyte macrophage colony-stimulating factor

Interleukin 3 receptor, subunit (Ligand-binding subunit),

Interleukin 5 receptor, subunit (Ligand-binding subunit),

GM-CSF receptor, subunit (Ligand-binding subunit),

IL-3 (IL3, P08700)

IL-5 (IL5, P05113)

G-CSF (CSF3, P09919), GM-CSF (CSF2, P04141)

IL-6 receptor family

Ciliary neutrophic factor receptor

Interleukin-6 receptor, subunit

Interleukin-11 receptor, subunit

Interleukin-31 receptor, subunit

Ciliary neurotrophic factor receptor subunit

IL-6 (IL6, P05231)

IL-11 (IL11, P20809)

IL-31 (IL31, Q6EBC2)

CNTF (CNTF, P26441), CRCF1/CLCF1

Searchable database: http://www.guidetopharmacology.org/index.jsp

Cytokine receptor family 1679

Leukemia inhibitory factor receptor

Leukemia inhibitory factor receptor