Signals and Receptors

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Harbor Laboratory Press
Signals and Receptors

Carl-Henrik Heldin1, Benson Lu2, Ron Evans2, and J. Silvio Gutkind3
1
Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, SE-75124 Uppsala, Sweden
2
The Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037
3
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4340
Correspondence: c-h.heldin@licr.uu.se
SUMMARY
Communication between cells in a multicellular organism occurs by the production of ligands

( proteins, peptides, fatty acids, steroids, gases, and other low-molecular-weight compounds)
that are either secreted by cells or presented on their surface, and act on receptors on, or in,
other target cells. Such signals control cell growth, migration, survival, and differentiation.
Signaling receptors can be single-span plasma membrane receptors associated with tyrosine
or serine/threonine kinase activities, proteins with seven transmembrane domains, or intra-
cellular receptors. Ligand-activated receptors convey signals into the cell by activating signal-
ing pathways that ultimately affect cytosolic machineries or nuclear transcriptional programs
or by directly translocating to the nucleus to regulate transcription.
Outline
1 Introduction 6 Functions of nuclear receptors

2 Cell-surface receptors 7 Gases
3 The TNF receptor family 8 Concluding remarks
4 Cell adhesion receptors and References
mechanotransducers
5 Nuclear receptors
Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner
Additional Perspectives on Signal Transduction available at www.cshperspectives.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005900
Cite this article as Cold Spring Harb Perspect Biol 2016;8:a005900 1
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C.-H. Heldin et al.
1 INTRODUCTION immune system and also promote cell differentiation. Cy-

tokine receptors can be divided into two classes. The ex-
Cells within multicellular organisms need to communicate
tracellular domains of class I cytokine receptors contain
with each other to coordinate their growth, migration,
cytokine receptor homology domains (CHDs) consisting
survival, and differentiation. They do so by direct cell–
of two tandem fibronectin type III domains with a charac-
cell contact and secretion or release of molecules that
teristic WSXWS motif in the second (Liongue and Ward
bind to and activate receptors on the surface of or inside
2007). Based on the number of CHDs and the presence of
target cells. Such factors can stimulate the producer cell
other types of domains, the class I cytokine receptors can be
itself (autocrine stimulation), cells in the immediate vicin-
divided into five groups (Fig. 2), the growth hormone
ity ( paracrine stimulation), or cells in distant organs (en-
(GH) receptor being typical of the first group. Interferon
docrine stimulation). The signaling induced within target
receptors are typical of the 12-member class II cytokine
cells is important during embryonic development, as well
receptor family, which also have extracellular regions based
as in the adult, where it controls cell proliferation, differ-
on tandem fibronectin domains but differ from those of
entiation, the response to infection, and numerous organ-
class I receptors (Fig. 2) (Renauld 2003). Both classes of
ismal homeostatic mechanisms.
cytokine receptors have conserved box 1 and box 2 regions
Many cell-surface receptors contain an extracellular li-
in their intracellular regions, which bind to JAK family
gand-binding region, a single transmembrane segment, and
tyrosine kinases that are activated upon ligand binding.
an intracellular effector region, which may or may not have
The multisubunit antigen receptors on B cells and T cells
an associated enzyme activity. Some receptors contain
(Zikherman and Weiss 2009) and the Fc receptors present
multiple subunits that together form the ligand-binding
on macrophages, mast cells, basophils, and other immune
site. Others, including those encoded by the largest gene
cells (Nimmerjahn and Ravetch 2008) are also associated
family in the human genome, consist of a polypeptide
with intracellular tyrosine kinases; activation of these re-
that spans the cell membrane seven times. Finally, there
ceptors involves tyrosine phosphorylation by members of
are receptors that are located intracellularly and are acti-
the Src family, followed by docking and activation of SH2-
vated by ligands that cross the cell membrane, such as ste-
domain-containing Syk/Zap70 tyrosine kinases (see Sa-
roid hormones. Below, we describe the major families of
melson 2011; Cantrell 2014). Although receptors that
ligands and receptors and the signal transduction mecha-
have intrinsic tyrosine kinase activity and those associated
nisms they activate.
with tyrosine kinases are structurally different and bind
ligands of different kinds, the principles underlying their
2 CELL-SURFACE RECEPTORS activation and the intracellular signals they initiate are sim-
ilar (see below).
2.1 Receptors with Associated Protein Kinase
There is also a family of receptors that have intrinsic
Activity
serine/threonine kinase domains, and these respond to
Several types of cell-surface receptors contain or are asso- members of the transforming growth factor b (TGFb) fam-
ciated with kinase activities that respond to the binding of a ily (see Moustakas and Heldin 2009; Wrana 2013). The
ligand. Perhaps best understood are receptors with intrinsic human genome has only 12 genes encoding receptors of
protein tyrosine kinase domains. This receptor tyrosine this type (Fig. 3). These receptors have rather small cys-
kinase (RTK) family has more than 50 human members teine-rich extracellular domains; their intracellular do-
(Lemmon and Schlessinger 2010). RTKs have important mains are most often also small and consist mainly of the
roles in the regulation of embryonic development, as well as kinase domains. TGFb receptors mediate signaling events
in the regulation of tissue homeostasis in the adult. Each during embryonic development. Because they often inhibit
has an extracellular, ligand-binding region, which consists cell growth, they also exert a controlling function on the
of different combinations of various domains, such as Ig- immune system and other tissues.
like, fibronectin type III, and cysteine-rich domains. This is
linked to a single transmembrane segment and an intracel-
2.2 Ligands
lular region that includes a tyrosine kinase domain. Based
on their structural features, RTKs can be divided into 20 Each of these different receptor types responds to a sub-
subfamilies (Fig. 1), a well-studied example being the epi- family of structurally similar ligands. The ligands are nor-
dermal growth factor (EGF) receptors (EGFRs). mally small monomeric, dimeric, or trimeric proteins,
Members of the cytokine receptor family in contrast often derived by proteolytic processing from larger precur-
lack intrinsic kinase activity but associate with intracellular sors, some of which are transmembrane proteins. There is
kinases. They have important roles in the regulation of the not a strict specificity in ligand–receptor interactions with-
2 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a005900

EGFR InsR PDGFRα VEGFR1/ FGFR1 PTK7/ TrkA Rot1 MuSk Met AxI Tie1 EphA1-8 Ret Ryk DDR1 Ros LMR1 ALK SuRTK106/
ErbB2 IGF1R PDGFRβ FIt1 FGFR2 CCK4 TrkB Ror2 Ron Mer Tie2 EphA10 DDR2 LMR2 LTK STYK1
ErbB3 InsRR CSF1R/ VEGFR2/ FGFR3 TrkC Tyro3 EphB1-4 LMR3
ErbB4 Fms KDR FGFR4 EphB6
Kit/SCFR VEGFR3/
FIt3/FIk2 FIt4
Tyrosine L Cysteine- Fibronectin Leucine- Cadherin Discoidin Ig EGF-like Kringle

kinase rich type III rich
SAM Psi WIF Ephrin Fz Ldla YMTD Acid Sema Mam

binding propeller box
Figure 1. Receptor tyrosine kinase (RTK) families. The 20 subfamilies of human RTKs and their characteristic
structural domains are shown. The individual members of each family are listed below. (From Lemmon and
Schlessinger 2010; adapted, with permission.)
in the families; normally each ligand binds to more than 2.3 Activation by Dimerization
one receptor, and each receptor binds more than one li-
A common theme for activation of kinase-associated recep-
gand. Although it is rare that ligands for completely differ-
tors is ligand-induced receptor dimerization or oligomeri-
ent types of receptors bind to kinase-associated receptors,
zation (Heldin 1995). The juxtaposition of the intracellular
examples do exist.4
kinase domains that occurs as a consequence allows auto-
phosphorylation in trans within the complex. For RTKs, the
autophosphorylation has two important consequences:
4
The Ryk and Ror families of RTK, for example, bind members of the Wnt it changes the conformation of the kinase domains, leading
family. Ryk has a Wnt inhibitory factor-1 (WIF1) domain, and the two Ror to an increase in their kinase activities; and it produces
receptors have cysteine-rich domains related to a domain in the Frizzled
family of serpentine receptors to which ligands of the Wnt family bind docking sites ( phosphorylated sequences) for intracellular
(van Amerongen et al. 2008). signaling molecules containing SH2 or PTB domains (see

C.-H. Heldin et al.
Class I Class II
Ig
CHD
FNIII
Box 1
Box 2
EPOR βC IL6Rα Gp130 LIFR Interferon receptors

GHR MPL G-CSFR OSMR IL10R
PRLR
IL4R
Figure 2. Cytokine receptor families. The structural features of the five subfamilies of class I and class II cytokine
receptors are depicted. The characteristic cytokine homology domains (CHDs) with their four cysteine residues
(blue lines) and a WW motif (green line), as well as the box 1 and box 2 regions (red bands), Ig-like domains, and
FNIII domains are shown.
Lee and Yaffe 2014). The autophosphorylation that controls active site of the kinase when unphosphorylated. Excep-
the kinase activity occurs on residues in various regions of tions are Ret and the four members of the EGFR family
the receptors. Most RTKs are phosphorylated in the activa- that can be activated without phosphorylation in their ac-
tion loops of the kinases, that is, a flexible loop of the car- tivation loops (Lemmon and Schlessinger 2010). Several
boxy-terminal domain, which can fold back and block the RTKs are activated by phosphorylation in the juxtamem-
A TGFβRI TGFβRII
B
Cysteine-rich ALK5/ TGFβR1
region ALK4/ActRIB
Extracellular ALK7
ALK3/ BMPR1A Type I receptors
GS domain Intracellular ALK6/ BMPR1B
ALK1
ALK2
ActRIIA
Serine/threonine ActRIIB
Type II receptors
kinase domain TGFβRII
BMPRII
MIS/AMHRII
Figure 3. Serine/threonine kinase receptors. (A) The structural features of type I (TGFbRI) and type II (TGFbRII)
serine/threonine kinase receptors. (B) The different members of the type I and type II receptor subfamilies and their
evolutionary relations. Act, Activin; ALK, activin-receptor-like kinase.

brane region, including MuSK, Flt3, Kit, and Eph family A TrkA
B KIT
members. Moreover, Tie2, platelet-derived growth factor
(PDGF) b receptor (PDGFRb) and Ron have been shown D1
to be activated by phosphorylation of their carboxy-termi- LRR
nal tails. In each case, autophosphorylation causes a change D2
in conformation that opens up the active site of the kinase. lg-C1
Interestingly, a phosphorylation-independent mechanism
for activation of EGFR kinase activity has been elucidated: D3
the carboxy-terminal lobe of one kinase domain makes SCF
lg-C2
contact with the amino-terminal lobe of the other kinase D4
domain in the dimer and thereby activates it (Zhang et al. NGF
2006). The juxtamembrane region of the receptor, which in
D5
other RTKs has an inhibitory role, is needed to stabilize this
C
dimeric interaction (Jura et al. 2009; Red Brewer et al. 2009).
FGFR D
Different ligands use different mechanisms to cause re-
ErbB
ceptor dimerization. Thus, GH is a monomeric ligand that
dimerizes its receptors by inducing formation of an asym- HSPG/ D1 DII
metric complex containing one ligand and two receptors heparin DI

D2
(De Vos et al. 1992). EGF is also a monomeric factor, but
EGF
EGF DIII
each molecule binds to a single receptor molecule, causing a
FGF
conformational change that promotes direct binding of two
ligand-bound receptors (Fig. 4) (Burgess et al. 2003). Sim- D3 DIV
ilarly, dimeric ligands can induce symmetric 2:2 ligand–
receptor complexes. In the case of nerve growth factor Figure 4. Schematic illustration of different modes of dimerization of
(NGF), the ligand itself is solely responsible for the dimer- RTKs. (A) Some dimeric ligands, such as nerve growth factor (NGF),
ization (Wehrman et al. 2007); in the case of Kit and the bind to receptors in a symmetric manner, but the receptors do not
PDGFRs, the ligand-induced receptor dimerization is sta- contact each other. (B) Other dimeric ligands, such as stem cell factor
bilized by direct interactions between the receptors (Yuzawa (SCF), also bind to RTKs in a symmetric manner, but the receptor
dimer is in addition stabilized by direct receptor–receptor interac-
et al. 2007). In other cases, accessory molecules are needed tions. (C) In the case of fibroblast growth factor (FGF), a ternary
to stabilize dimerization; that is, heparin or heparan sulfate complex involving the ligand, the receptor, and heparin/heparin sul-
stabilizes fibroblast growth factor (FGF)–induced receptor fate stabilizes the receptor dimer. (D) In the case of members of the
dimers by interacting with both FGF and FGF-receptor epidermal growth factor (EGF) receptor family such as ErbB, ligand
subunits (Lemmon and Schlessinger 2010). Recent work binding induces a conformational change in the extracellular domain
of the receptor that promotes direct receptor–receptor interactions.
on EGFR has shown that its activation requires an interac- (From Lemmon and Schlessinger 2010; adapted, with permission.)
tion between the amino-terminal parts of the transmem-
brane helices of the dimeric receptors, which promotes an
antiparallel interaction between the cytoplasmic juxta- tors (Heldin 1995). Because the downstream signaling
membrane segments and release of inhibition by the mem- pathways that are activated to a large extent depend on
brane (Arkhipov et al. 2013; Endres et al. 2013). the specific docking of SH2- or PTB-domain-containing
In addition to homodimerization of receptors, hetero- signaling molecules (see below and Lee and Yaffe 2014),
dimerization also often occurs. This is particularly com- differences in the autophosphorylation patterns of homo-
mon among cytokine receptors; a ligand-specific receptor dimeric versus heterodimeric receptor complexes will give
subunit often interacts with one or more common sub- rise to different combinatorial signals.
units, such as gp130, bc, or gc, to form a heterodimer, Serine/threonine kinase receptors present another var-
heterotrimer, or even more complicated multimer (Wang iation on this theme. These receptors are activated by li-
et al. 2009). Similarly, members of different RTK subfam- gand-induced assembly of two type I and two type II
ilies often form heterodimers. For instance, one member of receptors into heterotetrameric receptor complexes, in
the EGFR subfamily, ErbB2, cannot bind to ligand itself, which constitutively active type II receptors phosphorylate
but acts in heterodimers with other members of the family type I receptors in serine- and glycine-rich sequences just
(Yarden and Sliwkowski 2001). In the PDGFR family, dif- upstream of the kinase domains. In the TGFb type I recep-
ferent dimeric isoforms of the ligand induce formation of tor, this causes a change in conformation that prevents the
different dimeric complexes of PDGFa and PDGFb recep- inhibitory interaction of the receptor with the immuno-

C.-H. Heldin et al.
philin FK506-binding protein (FKBP12) and activates its bind to the carboxy-terminal tails of proteins containing
kinase (Kang et al. 2009). valine residues; and pleckstrin homology (PH) domains,
Note that certain receptors are present in dimeric com- which bind lipids present in membranes. Thus, large com-
plexes even in the absence of ligand; examples include the plexes of signaling proteins are transiently formed and
erythropoietin cytokine receptor, and the insulin and in- mediate signaling to cytoplasmic machinery (e.g., enzymes
sulin-like growth factor-1 (IGF1) receptors, RTKs that controlling the cytoskeleton and cell migration), as well as
actually occur as disulfide-bonded dimers. Here, ligand to the nucleus, where transcription is affected.
binding induces conformational changes that lead to acti- Note that the kinase domains of certain RTKs (e.g.,
vation of the receptor-associated kinase. Importantly, there ErbB3, CCK4, EphB6, and Ryk) lack critical catalytic resi-
are indications that reorientation of the intracellular re- dues normally found in kinases and thus have no, or very
gions of the receptors relative to each other in the dimer low, kinase activity. However, these receptors still have im-
is important for their activation (Jiang and Hunter 1999). portant roles in signal transduction, acting as phosphory-
latable scaffolds in heterodimers with other receptors.
There are also indications that the EGFRs can translo-
2.4 Signaling Downstream from Tyrosine-Kinase-
cate to the nucleus to regulate transcription (Lin et al.
Associated Receptors via SH2- or PTB-Domain-
2001). However, the functional significance of this needs
Containing Molecules
to be further clarified.
An important aspect of signaling by tyrosine-kinase-asso-
ciated receptors is the formation of multiprotein signaling
2.5 Downstream Signaling by Serine/Threonine
complexes (Pawson 2004). As mentioned above, SH2- or
Kinase Receptors
PTB-domain-containing proteins bind to specific phos-
phorylated tyrosine residues in the receptors themselves Serine/threonine kinase receptors activate members of the
or in scaffolding proteins associated with the receptors Smad transcription factor family (Wrana 2013); similar to
(see Lee and Yaffe 2014). Examples of the latter include STATs, these molecules oligomerize after phosphorylation
the four members of the insulin receptor substrate (IRS) and activation and then translocate to the nucleus, where
family, which bind to insulin and IGF1 receptors; FRS2- they induce transcription. In addition, serine/threonine
family protein molecules, which bind to FGF and NGF kinase receptors can activate non-Smad pathways. The
receptors; Gab molecules, which bind to several RTKs; TGFb type I receptor, for example, can autophosphorylate
and SLP76 and LAT, which bind to antigen receptors. on tyrosine residues, which bind to the adaptor Shc, lead-
Some of the proteins that bind to these sequences con- ing to activation of Ras and the ERK1/2 mitogen-activated
tain intrinsic enzymatic activities, for example, the tyrosine protein kinase (MAPK) pathway (see Morrison 2012).
kinases of the Src family, the tyrosine phosphatases of the Moreover, the p38 MAPK pathway is activated via binding
SHP family, GTPase-activating proteins (GAPs) that regu- of the ubiquitin ligase TRAF6 to the TGFb type I receptor
late Ras family GTPases, the ubiquitin ligase Cbl, and phos- (Kang et al. 2009). In addition to activating the type
pholipase C (PLC) g. Others are proteins that form stable I receptor, the TGFb type II receptor also contributes
complexes with enzymes, for example, the regulatory p85 to signaling by phosphorylating the polarity complex pro-
subunit of type 1 phosphoinositide 3-kinase (PI3K), which tein PAR6 (Ozdamar et al. 2005; McCaffrey and Macara
forms a complex with the catalytic p110 subunit, and Grb2, 2012).
which forms a complex with SOS1, a guanine nucleotide
exchange factor (GEF) that stimulates Ras. Cytokine recep-
2.6 Interaction with Coreceptors
tors and some RTKs also activate STAT molecules, which
translocate to the nucleus, where they act as transcription Several RTKs form complexes with nonkinase receptors,
factors (see Harrison 2012). Finally, SH2-/SH3-domain- such as the hyaluronan receptor CD44 and integrins, which
containing adaptor molecules (e.g., Shc, Nck, and Crk) bind to extracellular matrix molecules. Such interactions
bind to certain tyrosine phosphorylated sites in the re- can modulate their signaling. Similarly, the heparan sulfate
ceptors or associated molecules and form bridges to other proteoglycan agrin activates MuSK receptors by binding to
signaling molecules, including the enzymes mentioned low-density lipoprotein (LDL)-receptor-related protein 4
above. (LRP4); thus, LRP4 acts as a coreceptor for MuSK (Kim
Many of the signaling proteins that bind to the recep- et al. 2008). Another example is glial-ceU-derived neuro-
tors also contain domains that mediate interactions with trophic factor (GDNF) receptor a, a glycosylphosphatidy-
other molecules. These include SH3 domains, which bind linositol (GPI)-anchored molecule needed for GDNF to
proline-rich motifs in proteins; PDZ domains, which bind to and activate Ret receptors (Schlee et al. 2006).

2.7 Feedback and Amplification Mechanisms cases, internalization is even necessary for the receptors to
interact with signaling molecules on intracellular endo-
Signaling via kinase-associated receptors is controlled by
somes (Miaczynska et al. 2004). Examples include TGFb
multiple feedback mechanisms to ensure an appropriate
receptors, which need to be internalized to interact with
level. Thus, many tyrosine kinase and cytokine receptors
Smad molecules presented to the receptors by SARA and
bind protein tyrosine phosphatases (PTPs), including
endofin proteins. These proteins reside on endosomes, their
SHP1 and SHP2, that contain SH2 domains. Through
FYVE domains binding to phosphatidylinositol 3-phos-
dephosphorylation of specific tyrosine residues, PTPs mod-
phate (PI3P), a phospholipid that is enriched in endosomal
ulate signaling quantitatively as well as qualitatively (Lem-
membranes (Tsukazaki et al. 1998). Signaling is interrupted
mon and Schlessinger 2010).
when the pH of the endosomes becomes so low that the
Another example is activation of the small G protein
ligand dissociates; at this stage, receptors are dephosphor-
Ras, which occurs by docking of the GEF SOS1 in complex
ylated and recycle back to the cell surface. Alternatively, the
with the adaptor Grb2 (see Lee and Yaffe 2014). PDGFRb
receptors are recognized by components of the endosomal
and possibly other receptors simultaneously bind the Ras-
sorting complex required for transport (ESCRT) machin-
GAP molecules via another phosphorylated tyrosine resi-
ery, which facilitates translocation to multivesicular bodies
due, which counteracts Ras activation by promoting hy-
and degradation in lysosomes (Raiborg and Stenmark
drolysis of bound GTP.
2009). The latter route is promoted by ubiquitylation of
In addition, another downstream target of receptor sig-
the receptors by Cbl or other ubiquitin ligases.
naling, protein kinase C (PKC), is involved in feedback con-
trol of certain RTKs, including EGFR, the insulin receptor,
Met, and Kit. Activation of PLCg leads to production 2.9 Kinase-Associated Receptors and Disease
of diacylglycerol (DAG) and increases in intracellular calci-
Because tyrosine-kinase-associated receptors often stimu-
um levels, which activate the classical isoforms of PKC (see
late cell proliferation and survival, overactivity of these
Newton et al. 2014). Phosphorylation of the receptors by
receptors is linked to the development of cancer and other
PKC subsequently inhibits the kinase activity of the
diseases characterized by excess cell proliferation, such as
receptors.
inflammatory and fibrotic conditions. There are several
After the induction of immediate-early genes encoding
examples of gain-of-function mutations in RTKs that oc-
various effector molecules by signaling to the nucleus,
cur in malignancies (Lengyel et al. 2007; Sever and Brugge
RTKs induce the expression of delayed-early genes, many
2014). Point mutations in Kit and PDGFRa have been
of which encode proteins that suppress signaling. Examples
found in gastric intestinal stromal tumors, and the kinase
include NAB2, which binds to and inhibits EGFR; FOSL1,
domains of PDGFRs and FGFRs occur as constitutively
which binds to and inhibits AP1 transcription factors;
active cytoplasmic fusion proteins in several rare leukemias.
Id2, which inhibits the TCF transcription complex; DUSPs,
Moreover, the ERBB2 gene is amplified in 20% of breast
which dephosphorylate and inactivate MAPKs; and ZFP36,
cancers, and a mutated version of the EGFR gene is ampli-
which recognizes AU-motifs in the 3′ ends of mRNA mol-
fied in 30% of glioblastoma cases.
ecules and causes their degradation (Amit et al. 2007).
Because overactivity of these receptors is common in
Similarly, TGFb receptors and cytokine receptors induce
malignancies, several antagonists have been developed, in-
Smad7 (Moustakas and Heldin 2009) and SOCS proteins
cluding inhibitory antibodies, ligand traps, and low-mo-
(Yoshimura et al. 2003), respectively, which exert negative-
lecular-weight kinase inhibitors. Several of these are now
feedback control by promoting ubiquitin-dependent deg-
used routinely in the clinic or are undergoing clinical trials.
radation of receptors by targeting receptor-containing ves-
The serine/threonine kinase receptors often relay
icles to lysosomes (see below).
growth inhibitory and apoptotic signals and therefore
have tumor-suppressive effects. Thus, loss-of-function mu-
2.8 Endocytosis of Kinase-Associated Receptors
tations of TGFb type I and type II receptors have been
After ligand binding, kinase-associated receptors are inter- observed in some cancers (e.g., colorectal carcinomas).
nalized into the cell via clathrin-dependent or clathrin-in-
dependent pathways (Zwang and Yarden 2009). Whereas
2.10 Receptors Activated by Proteolytic Cleavage
internalization of RTKs is induced by ligand binding, inter-
nalization of serine/threonine receptors is constitutive and The highly conserved Notch family of receptors consists of
independent of ligand binding. Internalization has both four members, which have important roles during embry-
positive and negative effects on signaling. Thus, when pre- onic development and tissue renewal (Kopan and Ilagan
sent in endosomes, the receptors are still active; in some 2009). The Notch receptors are single-pass transmembrane

C.-H. Heldin et al.
proteins with large extracellular domains containing mul- mune responses, multiple developmental processes, and
tiple EGF-like repeats. They are cleaved extracellularly by stem cell function and maintenance (Pierce et al. 2002;
furin-like proteases during transit to the plasma membrane Dorsam and Gutkind 2007). Reflecting this remarkable
to create a heterodimer held together by noncovalent in- multiplicity of activities, GPCR dysregulation contributes
teractions (Kopan 2012). to some of the most prevalent human diseases. Indeed,
There are five canonical Notch ligands (Delta-ligand- GPCRs are the direct or indirect target of .50% of all
like 1, 3, and 4, and Jagged 1 and 2). These are also single- available medicines (Flower 1999; Pierce et al. 2002).
pass transmembrane proteins with extracellular EGF-like
regions and other domains present on neighboring cells.
2.12 A Shared Heptahelical Structure
The Notch receptor is normally triggered upon cell–cell
Transduces Signals Initiated by Highly
contact. Notch activation involves a series of proteolytic
Diverse Molecular Agonists
events. Ligand binding induces cleavage of Notch by
ADAM metalloproteases at a site about 12 amino acid res- GPCRs are characterized by the presence of an extracellular
idues outside the transmembrane domain. Removal of the amino terminus, an intracellular carboxy-terminal tail, and
extracellular domain allows an intramembrane cleavage by a shared structural core composed of seven transmembrane
g-secretase, which causes release of the intracellular do- a helices that weave in and out of the membrane, thus
main (ICD) of Notch. Because the ICD has a nuclear lo- forming three intracellular and three extracellular loops
calization sequence, it translocates to the nucleus, where it, (Fig. 5) (Pierce et al. 2002). They are regulated by a diverse
together with the DNA-binding protein RBPjk/CBF-1 and array of agonists, as small as photons, ions, nucleotides,
certain coactivators and corepressors (together referred to amino acids, biogenic amines, bioactive lipids, and glucose
as CSL), regulates transcription of target genes via its trans- metabolites, and as large as chemokines, glycoproteins, and
activation domain. Because the Notch ligands are mem- proteases. They can be grouped into three classes and sub-
brane-associated, signaling may also be induced in the families of these according to the structural features in-
ligand-bearing cells after binding to Notch. volved in ligand–receptor recognition and subsequent
Some RTK receptors (Ni et al. 2001) and the type I TGFb stimulation (Fig. 5).
receptor (Mu et al. 2011) are also subjected to sequential In class A GPCRs, the ligand-binding site is deep within
cleavage by metalloproteases and g-secretase. The intracel- the transmembrane domains in subfamily 1, which in-
lular region of the receptors can then translocate to the cludes most receptors for small molecules, such as neuro-
nucleus to regulate transcription. Meanwhile, the extracel- transmitters, lipid mediators, and odorants. Subfamily 2
lular portion of the receptor is liberated and can negatively members are activated by protein ligands, such as chemo-
regulate signaling by acting as a decoy for ligand (Ancot et al. kines and the tethered ligand resulting from thrombin-me-
2009). In addition, some RTKs are classified as “dependence diated cleavage of the protease-activated receptor 1 (PAR1)
receptors.” When they are not occupied by ligand, they can receptor. Subfamily 3 members have a very long extracel-
be cleaved by caspases (a group of proteases that control lular domain, which binds to leuteinizing hormone (LH;
apoptosis) to generate fragments with apoptotic activity. also known as lutropin), thyroid-stimulating hormone
For example, fragments of EGFR, ErbB2, Ret, Met, TrkC, (TSH), and follicle-stimulating hormone (FSH) (Korn-
ALK, and EphA4 have apoptotic effects, which contrast with bluth and Fissore 2014). This subfamily also includes
the normal antiapoptotic effects of the full-length receptors LGR5, LGR6, and LGR7, which are GPCR-like receptors
stimulated by their ligands (Ancot et al. 2009). involved in adult stem cell specification and function
(Hsu et al. 2000; Leushacke and Barker 2011). The class B
GPCRs are activated by high-molecular-weight hormones
2.11 G-Protein-Coupled Receptors
(e.g., glucagon, secretin, and vasoactive intestinal peptide
Approximately 2% of all genes in the human genome en- [VIP]), whereas class C GPCRs include metabotropic glu-
code G-protein-coupled receptors (GPCRs), which repre- tamate receptors, calcium-sensing receptors, g-amino bu-
sent the largest family of cell-surface molecules involved in tyric acid (GABA) B receptors, and receptors for taste
signal transmission. They are so called because their signals compounds. Although many class A and class B GPCRs
are transduced by heterotrimeric G proteins; members of can form homo- and heterodimers (Terrillon and Bouvier
the GPCR family regulate a wide range of key physiological 2004), dimer formation is obligatory for class C GPCRs
functions, including neurotransmission, blood pressure, (Kniazeff et al. 2011). The Frizzled family of receptors com-
cardiac activity, vascular integrity, hemostasis after tissue prises the “Frizzled” and “Smoothened” subfamilies, which
injury, glucose and lipid metabolism, sensory perception, are structurally distinct and have complex mechanisms of
regulation of endocrine and exocrine gland function, im- agonist activation (Ingham 2012; Lim and Nusse 2013).

Class A
1 2 3
Class B Class C
Frizzled Smoothened
Wnt
Frizzled Hedgehog Patched Smoothened
LRP6
Figure 5. GPCRs use distinct structural features for ligand recognition. GPCRs have been classified based on their
sequence similarities and ligand-binding properties. In class A GPCRs, the largest group, the ligand-binding site is
deep within the transmembrane domains in subfamily 1. It involves interactions with the amino terminus, the
extracellular loops, and the transmembrane domains in subfamily 2. The ligand-binding site is in the long extracellular
domain in subfamily 3. Class B GPCRs are activated by high-molecular-weight hormones, which bind to the ligand-
binding site within the long amino-terminal region, as well as some of the extracellular loops. Class C GPCRs are
characterized by a very long amino terminus that shares some sequence similarity with periplasmic bacterial proteins;
activation involves obligatory dimerization. The Frizzled family of receptors contains the Frizzled and “Smoothened”
subfamilies, which are structurally distinct and have complex mechanisms of agonist activation. Wnt binds to and
activates Frizzled through an interaction with a cysteine-rich amino-terminal region, whereas low-density lipopro-
tein-receptor-related protein 5 (LRP5) or LRP6 (single-transmembrane-span proteins) acts as a coreceptor (Lim and
Nusse 2013). When Hedgehog binds to Patched, a negative regulatory effect of Patched on Smoothened activity is
relieved, and Smoothened regulates both G-protein-dependent and -independent signals (Ingham 2012).
2.13 GPCR Activation, Trafficking, and G-Protein- the exchange of GDP bound to the a subunit for GTP,
Coupling Specificity causing release of Gbg (Lee and Yaffe 2014). A single li-
gand-bound GPCR can activate several G proteins, provid-
The heterotrimeric G proteins that relay signals from ing the first layer of signal amplification. The GTP-bound
GPCRs are associated with the underside of the plasma Ga subunits and Gbg subunits can then promote the ac-
membrane and are composed of an a subunit and a bg tivation of a variety of downstream effectors, stimulating a
dimer. Agonist-activated GPCRs act as GEFs that catalyze network of signaling events that is highly dependent on the

C.-H. Heldin et al.
G-protein-coupling specificity of each receptor (Fig. 6). loses contact with TM3, and moves closer to TM5. The
The human G-protein a subunits are encoded by 16 dis- consequent conformational changes in the intracytoplas-
tinct genes and can be divided into four subfamilies: Gas mic loops lead to the formation of a new pocket between
(Gas and Gaolf ), Gai (Gat, Gagust, Gai1-3, Gao, and Gaz), TM3, TM5, and TM6, which binds to the carboxyl termi-
Gaq (Gaq, Ga11, Ga14, and Ga15/16), and Ga12 (Ga12 and nus of the Ga subunits, leading to G-protein activation by
Ga13) (Fig. 6) (Cabrera-Vera et al. 2003). A single GPCR promoting the release of GDP and its exchange for GTP
can couple to either one or more than one family of Ga (Kobilka 2011). Ligands that bind and stabilize the recep-
subunits. Five different b subunits and 12 g subunits that tors in conformations other than this fully activated state
form functional bg dimers have been described. act as partial agonists, and they provoke a more limited G-
Studies of the structural perturbations caused by ligand protein activation and hence a restricted response. Ligands
binding to class A GPCRs reveal that agonist binding causes that stabilize the inactive conformation of the GPCR act
a contraction of a ligand-binding pocket located within the as classical antagonists or inverse agonists. There is now a
transmembrane a-helical regions. In particular, upon li- great interest in the development of novel drugs that act as
gand binding, the transmembrane (TM) a helix 6 moves allosteric modulators by binding at a site distinct from that
outward from the center of the transmembrane bundle, to which the natural GPCR ligands bind. This new gener-
GPCR
Ion channels
PIP2 PIP3
βγ α βγ Pl3K
α
GTP GTP
GDP βγ β-Arrestin
GDP
α Rac/
AKT
Src
GTP Cdc42 GRK
GEFS
mTOR
αi αs α αq
αt, αi1-3, αo, αz αs, αolf α12, α13 αq, α11, α14, α15/16 Rac
ASK1 Raf
β-Arrestin
β-Arrestin
PIP2 MKK4 MEK
PLCβ
AC JNK3
IP3 ERK
ATP Rac/ Ras

Rap Rho
Cdc42 GEFS
GEFS GEFS 2+
DAG
cAMP GEFS Ca
phospho-
PKA Rap Rho Rac Cdc42 CaMK PKC Ras
PDEs lipases
Multiple cytosolic and nuclear effects Multiple cytosolic and nuclear effects
Figure 6. Regulation of classical second messenger systems and Ras and Rho GTPases by GPCRs. Agonist-activated
GPCRs promote the dissociation of GDP bound to the a subunit pf heterotrimeric G proteins and its replacement
by GTP. Ga and Gbg subunits can then activate numerous downstream effectors. The 16 human G protein a
subunits can be divided into the four subfamilies shown, and a single GPCR can couple to one or more families of
Ga subunits. Downstream effectors regulated by their targets include a variety of second messenger systems, as well
as members of the Ras and Rho families of small GTP-binding proteins, which, in turn, control the activity of
multiple MAPKs, including ERK, JNK, p38, and ERK5. G-protein-dependent activation of these by GPCRs and b-
arrestin-mediated G-protein-independent activation of ERK and JNK can have multiple effects in the cytosol.
MAPKs also translocate to the nucleus, where they regulate gene expression. Activation of the PI3K–Akt and
mTOR pathways plays a central role in the regulation of cell metabolism, migration, growth, and survival by GPCRs.

ation of pharmacological agents changes the receptor con- 2.15 GPCRs Regulate a Network of Ras- and
formation, thereby modifying the affinity and/or efficacy Rho-Related GTPases, MAPK Cascades,
of the endogenous ligands (May et al. 2007). Note that the and PI3K-Regulated Signaling Circuits
nature of the agonist binding can impact receptor confor-
mation, thus biasing the choice of G protein and hence the GPCRs stimulate pathways that control cell migration, sur-
signaling output. vival, and growth in part by activating MAPKs, a group of
highly related proline-targeted serine/threonine kinases
that link multiple cell-surface receptors to transcription
2.14 Regulation of Classical Second Messenger
factors. MAPKs include ERK1/2, JNK1-3, p38a-d, and
Systems by G Proteins and Their Linked GPCRs
ERK5 MAPKs (Gutkind 1998; Morrison 2012).
Many of the immediate actions of GPCRs involve the rapid The small GTPase Ras, tyrosine kinases, PI3Ks, PKCs,
generation of second messengers (Fig. 6). Gas stimulates and arrestins can act downstream from GPCRs to pro-
adenylyl cyclases, which increases the cytosolic levels of mote the activation of ERK1/2 in a cell-specific fashion
cAMP, whereas Gai inhibits adenylyl cyclases and hence (for review, see Gutkind 2000). The JNK cascade is acti-
decreases cAMP levels as a result of tonic phosphodiester- vated downstream from the small G proteins Rac, Rho,
ase activity. The different adenylyl cyclase isoforms appear and Cdc42 (Coso et al. 1995). Indeed, Rac and Cdc42 can
to be distinctly regulated by Gas and Gai, as well as by Gbg mediate signaling of Gbg dimers and Ga12, Ga13, Gaq, and
subunits, intracellular calcium, and PKCs (Taussig and Gil- Gai to JNK (Gutkind 2000; Yamauchi et al. 2000). Many
man 1995). Thus, the effects of different GPCR agonists on GPCRs coupled to Gi activate Rac and JNK through the
the intracellular levels of cAMP are highly dependent on the direct interaction of Gbg subunits with the P-REX1/2
adenylyl cyclases expressed in a given cell type. Gat and family of Rac-GEFs (Welch et al. 2002; Rosenfeldt et al.
Gagust (also known as transducin and gustducin, respec- 2004). Similarly, Gaq activates Rho GTPases, and hence
tively) activate phosphodiesterases in the visual system and JNK, through direct interaction with p63-RhoGEF and
gustative papillae, respectively, thus decreasing the cyto- Trio (Lutz et al. 2007). Ga12 and Ga13 bind to and act on
plasmic levels of cGMP by converting it to GMP (Cab- three GEFs—p115-RhoGEF, PDZ-RhoGEF, and LARG—to
rera-Vera et al. 2003). Members of the Gaq family bind to promote the activation of Rho downstream from GPCRs
and activate phospholipase Cb, which cleaves phosphati- (Hart et al. 1998; Fukuhara et al. 2001). Additional GEFs can
dylinositol 4,5-bisphosphate (PIP2) into DAG and inositol also contribute to this network. How GPCRs activate p38
1,4,5-trisphosphate (IP3). The latter causes an increase in and ERK5 is much less clear, but, in general, these MAPKs
cytosolic calcium levels by promoting the release of calcium are activated primarily by Gaq, Ga12/13, and Gbg dimers
from intracellular stores and also subsequent calcium in- (Gutkind 2000).
flux into the cells, whereas DAG activates PKC (Hubbard Although human cancer-associated viruses express
and Hepler 2006; Julius and Nathans 2012; Sassone-Corsi constitutively active viral GPCRs, emerging data from
2012; Newton et al. 2014). deep sequencing studies have revealed that a large fraction
The released Gbg dimers can independently activate of human malignancies harbour mutations in GPCRs and
many signaling molecules, including PLCb, adenylyl cy- G-protein a subunits (O’Hayre et al. 2013). This has in-
clases, and ion channels ( particularly the GIRK family of creased the interest in the molecular mechanisms by which
potassium channels). Although, in principle, the activation G proteins and GPCRs control normal and cancer cell
of any G protein by GPCRs should result in the release of growth. Recent findings suggest that although GPCRs can
Gbg dimers and hence activation of their downstream tar- stimulate multiple diffusible-second-messenger-generat-
gets, Gi and Go are often the most highly expressed G pro- ing systems, their ability to promote normal and aberrant
teins and represent the most frequent source of free Gbg cell proliferation often relies on the persistent activation
complexes. of Rho GTPases and MAPK cascades based on the direct
The targets of diffusible second messengers activated by interaction of Ga subunits with RhoGEFs. The MAPKs
G proteins include a large number of ion channels, calci- regulate the activity of nuclear transcription factors and
um-sensitive enzymes, and kinases such as PKA, PKC, coactivators, such as Jun, Fos, and YAP (Yu et al. 2012;
cGMP-dependent kinase (PKG), and calcium-/calmodu- Vaqué et al. 2013).
lin-dependent kinases (CaMKs), which are stimulated by Activation of the PI3K–Akt and mTOR pathways plays
cAMP, calcium/DAG, cGMP, and calcium, respectively. a central role in cell metabolism, migration, growth, and
Heterotrimeric G proteins can also regulate other effectors, survival (Zoncu et al. 2011). PI3K generates 3′ -phosphor-
including signaling molecules that activate kinase cascades ylated inositol phosphates that participate in activation of
and small GTPases. the kinase Akt and mTOR, which relay downstream signals

C.-H. Heldin et al.
(Hemmings and Restuccia 2012; Laplante and Sabatini but are now believed to scaffold a wide variety of signaling
2012). PI3Kg shows restricted tissue distribution and is complexes (Luttrell and Gesty-Palmer 2010; Rajagopal et al.
activated specifically by GPCRs by the direct interaction 2010). In particular (Andreeva et al. 2007), they can interact
of its catalytic ( p110g) and regulatory ( p101) subunits with Src family kinases as well as multiple serine/threonine
with Gbg subunits (Lopez-Ilasaca et al. 1997). PI3Kg is kinases, small GTPases and their GEFs, E3 ubiquitin ligases,
involved in the chemokine-induced migration of leuko- phosphodiesterases, and transcription factors (Luttrell and
cytes and plays significant roles in innate immunity (Costa Gesty-Palmer 2010; Rajagopal et al. 2010). b-Arrestins can
et al. 2011). In cells lacking PI3Kg expression, GPCRs can act downstream from GPCRs within endocytic vesicles in a
use PI3Kb to stimulate phosphatidylinositol-(3,4,5)-tris- pathway leading to the activation of ERK1/2 and JNK,
phosphate (PIP3) synthesis (Ciraolo et al. 2008). particularly in response to b-arrestin-biased agonists for
some GPCRs, thus initiating intracellular signaling inde-
pendently of the activation of heterotrimeric G proteins
2.16 GPCR-Interacting Proteins in Receptor
(Rajagopal et al. 2010). Interestingly, b-arrestins can form
Compartmentalization, Trafficking, and
multimeric signaling complexes with ERK1/2 and JNK that
G-Protein-Independent Signaling
are retained in the cytosol, thus restricting the nuclear
GPCRs interact with a diverse array of proteins, which translocation of these MAPKs, which instead act on cyto-
regulate compartmentalization to plasma membrane mi- solic substrates (Fig. 6) (Rajagopal et al. 2010). Besides the
crodomains, endocytosis, trafficking between intracellular best-studied b-arrestins, a family of a-arrestins that are
compartments and the plasma membrane, and G-protein- conserved from budding yeast to humans has recently re-
independent signaling (see below). These include receptor- ceived increased attention because of their potential role in
activity-modifying proteins (RAMPs), GPCR-associated GPCR trafficking and degradation (Nabhan et al. 2010).
sorting proteins (GASPs), Homer, b-arrestins, arrestin-do-
main-containing proteins (ARRDCs), and DEP-domain
2.17 GPCR-Independent Activation of G Proteins
proteins (Ballon et al. 2006; Magalhaes et al. 2012).
RAMPs are single-transmembrane-span proteins that Heterotrimeric G proteins can be also activated in a GPCR-
associate with some class C GPCRs, such as the calcitonin independent fashion by a family of proteins known as ac-
receptor and calcitonin-like receptor. RAMPs facilitate the tivators of G-protein-mediated signaling (AGS proteins)
glycosylation of calcitonin family receptors in the en- (Blumer et al. 2007). These proteins substitute for GPCRs
doplasmic reticulum, thereby facilitating their expression by promoting nucleotide exchange on Ga subunits (e.g.,
at the cell surface, and remain associated at the plasma AGS1), or can regulate the physical interaction and locali-
membrane, where RAMPs contribute to ligand binding zation of G-protein subunits without affecting nucleotide
and receptor signaling (Bouschet et al. 2005). GASPs inter- exchange (e.g., AGS3, also known as LNG or PINS pro-
act with the carboxy-terminal tail of many GPCRs and are teins) (Blumer et al. 2007). The latter play an important
primarily involved in their postendocytic sorting (Whis- conserved role in cell polarity and polarized cell division
tler et al. 2002). Homer 1a-c, Homer 2, and Homer 3 rep- and share the presence of a GoLoco motif by which they
resent a class of proteins that harbor Enabled/VASP bind to Ga subunits to prevent nucleotide exchange (Wil-
homology (EVH)–like domains and bind to metabotropic lard et al. 2004).
glutamate receptors (mGluRs) through a carboxy-terminal
polyproline sequence (PPXXFP) (Bockaert and Pin 1999).
2.18 GPCR Signal Termination
GPCRs can also associate with molecules containing
protein –protein interaction domains, such as DEP, PDZ, Considerable attention has focused on mechanisms of ter-
WW, SH2, and SH3 domains (Lee and Yaffe 2014), as well mination of GPCR signaling, because persistent activation
as polyproline-containing regions (Bockaert and Pin 1999; occurs in many diseases (Pierce et al. 2002). This desensi-
Brzostowski and Kimmel 2001). These interactions facili- tization is highly regulated and occurs through several well-
tate the localization of GPCR-initiated signaling to specific understood mechanisms, including GPCR-targeted kinas-
cellular structures or membrane microdomains, including es known as GPCR kinases (GRKs), and more general sec-
the neuronal synapse, and also determine the signaling ond-messenger-regulated kinases, such as PKC and PKA.
output by favoring the activation of a subset of GPCR PKC and PKA phosphorylation uncouples receptors from
targets by increasing their local accumulation in the vicin- their respective G proteins, presumably by phosphorylat-
ity of the GPCR. ing G-protein-interaction sites or by recruiting arrestins
b-Arrestins were initially described as adaptor proteins (Benovic et al. 1985), thereby forming a negative-feedback
promoting the endocytosis of activated GPCRs (see below) loop. Activation of PKA and PKC can also result in the

heterologous desensitization of multiple GPCRs within a where they regulate defense against infection (see Newton
cell (Chuang et al. 1996). In contrast, GRKs phosphorylate and Dixit 2012); however, some members are expressed
only the activated or agonist-occupied form of the receptor, elsewhere, regulating hematopoiesis and morphogenesis.
primarily in the carboxy-terminal tail, which then binds Perturbation of signaling by TNFRs is implicated in several
arrestin dimers that can prevent G-protein interaction and diseases, including tumorigenesis, bone resorption, rheu-
promote the removal of the receptor from the cell surface matoid arthritis, and diabetes (Aggarwal 2003; Croft 2009).
by endocytosis (Shenoy and Lefkowitz 2011). Internalized Members of the TNFR family have an amino-terminal
receptors can be recycled back to the plasma membrane or extracellular region consisting of one to four cysteine-rich
degraded in lysosomes, a process influenced by the ability domains, each of which contains three conserved intra-
of ligand-bound receptors to interact with ubiquitin ligases chain disulfide bridges. These are linked to a single trans-
and a complex repertoire of sorting molecules (Hanyaloglu membrane segment and a cytoplasmic region that lacks
and von Zastrow 2008). Concomitantly, a family of regula- enzymatic activity (Locksley et al. 2001). Several receptors
tors of GPCR signaling (RGS) molecules act as GAPs on contain binding motifs for members of the TRAF family of
GTP-bound G-protein a subunits, accelerating GTP hy- ubiquitin ligases in their intracellular regions, and eight of
drolysis and hence signal termination (Berman and Gilman them contain death domains (DDs), which are involved in
1998). Signaling and inactivation are intertwined, because apoptotic signaling (Fig. 7). Some instead lack intracellular
molecules such as arrestins can also regulate GPCR signal- and/or transmembrane regions and act as decoy receptors.
ing specificity and/or localization (Shenoy and Lefkowitz The TNF family ligands are also transmembrane pro-
2011), and many G-protein targets include RGS domains teins but have extracellular carboxyl termini. Intriguingly,
or act as GAPs, thus acting as direct effectors that concom- these can be shed following cleavage by proteases, and some
itantly limit the duration of G-protein signaling. inhibit the effects of the membrane-bound ligand (Suda
et al. 1997). The ligands are characterized by a conserved
2.19 GPCR Signal Integration TNF homology domain that mediates receptor binding. An
exception is nerve growth factor (NGF), which in addition
GPCRs are best known for their ability to control the ac- to binding to an RTK also binds to p75, a member of the
tivity of adenylyl cyclases, phosphodiesterases, phospholi- TNFR family. Several ligands of this family bind to more
pases, ion channels, and ion transporters. The rapid than one receptor (Fig. 7).
regulation of these classical diffusible-second-messenger-
generating systems and their direct molecular targets is now
believed to represent a subset of the extensive repertoire of 3.2 Activation of TNFRs
molecular mechanisms deployed by GPCRs in physiolog- Most TNF family ligands are noncovalent trimers that form
ical and pathological contexts. Our recently gained under- symmetric 3:3 complexes with their receptors. Homomeric
standing of GPCR signaling circuitries, including GEFs, as well as heteromeric receptor complexes have been de-
Ras and Rho GTPases, MAPKs, PI3Ks, and their numerous scribed (Schneider et al. 1997). Preformed receptor oligo-
downstream cytosolic and nuclear targets, provide a more mers exist and TNFR1 and TNFR2 have a pre-ligand-
global view of the general systems by which these receptors binding assembly domain (PLAD) that is required for the
exert their numerous physiological and pathological roles. assembly of TNFR complexes (Chan et al. 2000). Whereas
Indeed, the final biological outcome of GPCR activation juxtaposition of the receptors is important for activation,
most likely results from the integration of the network of trimerization itself appears not to be necessary because
GPCR-initiated biochemical responses in each cellular con- there are examples of agonistic bivalent monoclonal anti-
text. A new, systems-level understanding may provide a bodies directed against the extracellular domain, and be-
molecular framework for the development of novel ap- cause one of the ligands, NGF, is a dimer.
proaches for therapeutic intervention in some of the
most prevalent human diseases.
3.3 Signaling via TNFRs
3 THE TNF RECEPTOR FAMILY The receptors that have DDs, including TNFR1, Fas (also
known as CD95), death receptor (DR) 3, DR4, DR5, DR6,
3.1 TNF Isoforms and TNF Receptors EDAR, and the p75 NGF receptor, induce apoptosis and
Tumor necrosis factor (TNF) belongs to a 19-member fam- necrosis of cells (Moquin and Chan 2010; Newton and
ily of structurally related factors that bind to the 29 mem- Dixit 2012; Green and Llambi 2014). Ligand-induced re-
bers of the TNF receptor (TNFR) family. Most TNF and ceptor activation leads to the formation of complexes re-
TNFR members are expressed in the immune system, ferred to as death-inducing signaling complexes (DISCs),

C.-H. Heldin et al.
TNFR1 221 TNFα
TNFR2 174 TNFβ
Fas 145 FasL
DCR3
DR3 193 VEGI
DR4 203 TRAIL
DR5 221
DCR1
DCR2 154
DR6 286 ?
EDAR 236 EDA-A1
NGFR 155 NGF
OPG
RANK 282 RANKL
LTβR 187 LTα/LTβ
FN14 28 TWEAK
HVEM 58 LIGHT
CD27 48 CD27
CD30 188 CD30
CD40 62 CD40
4-1BB 45 4-1BBL
OX40 36 OX40L
GITR 42 GITRL
BCMA 106 APRIL
TACI 106
BAFFR 82 BAFF
XEDAR 134 EDA-A2
TROY 233 ?
RELT 243 ?
Furin cleavage Metalloproteinase (TACE) cleavage Matrilysin cleavage TRAF1 binding TRAF2 binding
Cysteine-rich domain Death domain TRAF3 binding TRAF5 binding TRAF6 binding
TNF homology region
Figure 7. The tumor necrosis factor (TNF) receptor family. The structural features of the members of the TNF
receptor family (left) and their ligands (right) are shown. Cysteine-rich domains, death domains, and interaction
motifs for various members of the TRAF family are indicated. Cleavage sites for various proteases involved in
processing of the ligands are also shown. (From Aggarwal 2003; adapted, with permission.)
in which the receptor DDs interact with DDs in adaptor In addition to apoptosis, TNFRs control survival and
molecules such as TRADD and FADD. The protease pro- differentiation. Many of their effects are mediated by the
caspase 8 is also recruited to the DISC, triggering a caspase TRAF family of ubiquitin ligases, which stimulate NF-kB,
cascade that results in apoptosis. PI3K, and JNK and p38 MAPK pathways (Faustman and

Davis 2010). Activation of NF-kB is of central importance which integrins are maintained in an inactive state that en-
and occurs downstream from all members of the TNFR ables cells to circulate in the bloodstream without interact-
family, except the decoy receptors. Moreover, certain mem- ing with endothelial cells in the blood vessel wall, but quickly
bers of the TNFR family stimulate cell proliferation, for deploy their adhesive properties in response to immune cell
example, by activation of the ERK1/2 MAPK. activation and the coagulation cascade (Moser et al. 2009).
For example, cytokine-induced activation of the leukocyte
3.4 TNFRs and Disease integrin LFA1 (also known as aLb2) leads to its rapid bind-
ing to intercellular adhesion molecule (ICAM)-1, an adhe-
Overactivity of members of the TNFR family is seen in sion molecule expressed on the surface of activated
immune-related diseases, and encouraging results have endothelial cells, thereby stabilizing cell–cell interactions
been obtained using inhibitory anti-TNF antibodies or and facilitating the transmigration of circulating leukocytes
ligand traps in the treatment of Crohn’s disease (Suenaert through the endothelial cell layer into damaged tissues
et al. 2002) and rheumatoid arthritis (Feldmann and Maini (Moser et al. 2009). The integrins also provide important
2001). Similarly, blocking signaling via the receptors OX40, survival signals, because many cells undergo anoikis, a form
4-1BB, CD27, and DR3 is effective in various immune of programmed cell death, upon detaching from their sur-
diseases (Croft 2009). Promising attempts have also been rounding ECM (Frisch and Screaton 2001). Overall, integ-
made to induce apoptosis of cancer cells by treatment with rin-mediated cell adhesion controls cell migration, survival,
agonists of TNFR1, Fas, and TRAIL receptors (Fox et al. growth, and differentiation, whereas at the organismal level,
2010). integrins play fundamental roles in tissue morphogenesis
during development, and in the immune response, hemo-
4 CELL ADHESION RECEPTORS AND stasis, and tissue maintenance and repair (Hynes 2002;
MECHANOTRANSDUCERS Miranti and Brugge 2002; Devreotes and Horwitz 2013).
Each integrin is composed of a heterodimer of two
4.1 Mechanosensing Signaling through Integrins
transmembrane subunits (a and b). In humans, there are
Cells deploy multiple signaling mechanisms to sense the 18 a subunits (Fig. 8), which associate with eight different
biophysical properties of their surroundings and commu- b subunits to form at least 24 heterodimeric complexes
nicate with their neighboring cells. Integrins are perhaps displaying distinct ligand-binding specificities and signal-
the best known cell-surface receptors involved in these es- ing capacities. Some of these dimers are widely expressed,
sential processes. They function primarily in cell adhesion whereas others show more restricted distributions and can
to the extracellular matrix (ECM) or to other cells, the latter therefore have more specific biological functions. Integrins
through a repertoire of cell-surface ligands involved in typically have large extracellular regions, which interact
cell–cell interactions. Integrins accumulate at cell–ECM with cell-surface ligands and with specific sequence motifs
and cell–cell contact points and orchestrate the local as- in ECM proteins, such as the tripeptide RGD motif origi-
sembly of multimolecular structures known as adhesion nally described in fibronectin (Geiger et al. 2001; Hynes
complexes, often referred to as focal adhesions (FAs) or 2002). Some integrins are promiscuous and can bind to
adhesomes (Hynes 2002; Geiger and Yamada 2011). multiple ligands, for example, the ECM components vitro-
Integrins provide a link between the extracellular envi- nectin, fibrinogen, fibronectin, laminin, collagen, and te-
ronment and the intracellular cytoskeleton, and their dy- nascin. Other integrins show a more restricted binding
namic engagement at cell–ECM and cell–cell adhesions pattern or bind to other cell adhesion receptors—for ex-
results in the rapid activation of multiple intracellular sig- ample, ICAMs, vascular cell adhesion molecule (VCAM),
naling circuits, a process known as outside-in signaling and E-cadherin (see Table 1). Most integrins possess a rel-
(Hynes 2002; Miranti and Brugge 2002). In turn, the ad- atively short intracellular cytoplasmic domain (40–70 ami-
hesive properties of integrins and hence the strength of the no acids), with the exception of integrin b4, which has a
interactions with the ECM and other cells are regulated by a long cytoplasmic domain.
variety of signaling pathways, which impinge on the inter- The conformation of the integrin extracellular domains
action of integrins with a key cytoskeletal molecule, talin changes dramatically upon cell–ECM and cell–cell adhe-
(see below); this process is known as inside-out signaling sions (Shattil et al. 2010). This results in the separation of the
(Hynes 2002). Integrins can be regulated in this way by intracellularcytoplasmic tails, which lack enzymatic activity
signals from growth factors acting on RTKs and GPCRs, but instead act as platforms for the assembly of multimeric
as well as by inflammatory cytokines and bioactive lipids protein complexes that are involved in signal transduction
(Hynes 2002; Miranti and Brugge 2002). The latter is of (Shattil et al. 2010; Wehrle-Haller 2012) and link integrinsto
particular importance for immune cells and platelets, in the cytoskeleton. The direct binding of talin to the cytoplas-

C.-H. Heldin et al.
out signaling (Legate and Fassler 2009; Moser et al. 2009).

β5
β6 Tensin is recruited to FAs and helps to establish additional
β8 connections between integrins and actin fibers. Ultimately,
these multiple links between integrins and actin promote
α1
α2 αv β3 localized actin polymerization at sites of cell–ECM and
cell–cell contact. This allows rapid assembly and disassem-
α3 α11 bly of adhesion contacts and dynamic control of the cellular
β7 αIIb cytoskeleton during cell migration (Huttenlocher and Hor-
α4 β1 α10
witz 2011; Devreotes and Horwitz 2013).
FAs (Geiger and Yamada 2011) contain many cytoskel-
etal, adaptor, and signaling proteins. Among them, multi-
α5 α9
ple nonreceptor tyrosine kinases, including focal adhesion
α6 α8
kinase (FAK), the related proline-rich tyrosine kinase 2
α7 (Pyk2), Src, and Src-family kinases act both as signal trans-
ducers and as scaffolds (Fig. 9) (Miranti and Brugge 2002;
αE β4 Geiger and Yamada 2011). Activation of these tyrosine ki-
nases upon integrin ligation results in their autophosphor-
ylation and cross-phosphorylation at several tyrosine
residues, creating binding sites for multiple signaling pro-
teins. These include the adaptor protein Grb2, which leads
β2 to recruitment of SOS (a GEF for Ras) and the consequent
activation of Ras and the MAPK ERK1/2. In the case of
FAK, the phosphotyrosines recruit Src, Grb2, and the p85
αL αD
subunit of PI3Kvia their SH2 domains (Miranti and Brugge
2002; Legate et al. 2009; Shattil et al. 2010). The latter gen-
αM αX
Table 1. Ligands for a– b integrin heterodimers

Figure 8. The integrin family of cell adhesion receptors. Integrins are Integrin Representative ligands
composed of a heterodimer of two transmembrane a and b subunits.
The 18 a subunits and eight b subunits can form at least 24 hetero- a1b1 Collagen, laminin
dimeric complexes displaying distinct binding specificity and signal- a2b1 Collagen, laminin
ing capacity. (Adapted from Hynes 2002.) a3b1 Laminin, fibronectin
a4b1 VCAM-1, fibronectin, thrombospondin
a4b7 VCAM-1, fibronectin, MAdCAM-1
mic tails of most activated integrin b subunits is one of the a5b1 Fibronectin, neural adhesion molecule L1
earliest events after integrins bind to the ECM. This causes a6b1 Laminin
the local accumulation of PIP2 upon recruitment of the lipid a6b4 Laminin
kinase phosphatidylinositol 4-phosphate 5-kinase via its a7b1 Laminin
a8b1 Osteopontin, fibronectin, vitronectin, tenascin
interaction with talin and the subsequent recruitment of
a9b1 Tenascin, osteopontin, VCAM-1
vinculin to the nascent adhesions (Legate and Fassler a10b1 Collagen
2009; Moser et al. 2009; Shattil et al. 2010). This helps sta- a11b1 Collagen
bilize FAs, because integrin b subunits interact weakly with aEb1 E-cadherin
actin through talin in the absence of vinculin. Vinculin and aLb2 ICAM-1, ICAM-2, ICAM-3
talin also bind to a-actinin, which has a high affinity for aMb2 ICAM-1, ICAM-2, ICAM-4, fibrinogen
actin and hence helps strengthen the interactions between b aXb2 ICAM-1, fibrinogen
aDb2 ICAM-3, VCAM-1
integrins and actin filaments. Other molecules linking the b
aIIbb3 Fibrinogen, fibronectin, vitronectin,
subunits to actin include filamin, kindlins, migfilin, and thrombospondin, von Willebrand factor
integrin-linked kinase (ILK), a pseudokinase that bridges aVb3 Vitronectin, fibronectin, fibrinogen, osteopontin
b integrins and parvin, another actin-binding protein aVb5 Vitronectin
(Hynes 2002; Legate et al. 2009; Geiger and Yamada 2011). aVb6 Vitronectin, fibronectin
ILK stabilizes the FA by retaining integrins in a clustered aVb8 Fibronectin, laminin, collagen, vitronectin
state and by reinforcing the connection with the cytoskele- a6b4 Laminin
ton, whereas kindlins partner with talins in integrin inside- a4b7 VCAM-1, fibronectin

ECM
Outside-in Integrin RTK

signaling GPCR
in
ctin
Vincu
Talin
α-A
Kindli
FAK Zyxin n Gα Gβγ
ILK
lin
PI3K Inside-out
Src p130CAS signaling
Tensin CRK
Grb2 Paxillin
CK
Akt α-Pix
DO
SOS Cdc42
Ras Rac Rho
Cell survival
PAK
ERK
JNK
Actin
Cell motility
Cell proliferation
Cell survival
Figure 9. Integrin-based cell adhesion and signaling. Integrin engagement at cell-matrix adhesions or interaction
with a repertoire of cell-surface ligands results in the rapid assembly of a multifunctional protein network (Geiger
and Yamada 2011) containing many cytoskeletal, adaptor, and signaling proteins. This contributes to cell adhesion
and activates multiple signaling events. The adhesive properties of integrins are, in turn, regulated by a variety of
signaling pathways; this is known as inside-out signaling.
erates PIP3 at the plasma membrane, which recruits ILK, appropriately to mechanical cues. In addition to outside-in
Akt, and other proteins to the FA complex (Miranti and and inside-out signaling, integrin activation can also in-
Brugge 2002; Shattil et al. 2010; Lee and Yaffe 2014). Akt duce the rapid clustering of multiple RTKs, such as EGFR,
relays prosurvival and growth-promoting signals. A direct PDGFR, and FGFR (Miyamoto et al. 1996; Geiger and
substrate of FAK, paxillin, acts as a multidomain adaptor Yamada 2011). This enhances signaling in response to cell
protein that forms a scaffold organizing a variety of signal- adhesion. Finally, note that rather than being rigid intra-
ing molecules, including Src, ILK, Crk, and vinculin (Mi- cellular structures, most FAs are dynamic (Devreotes and
ranti and Brugge 2002; Geiger and Yamada 2011). Crk is an Horwitz 2013), and regulation of their multiple compo-
adaptor protein that binds to tyrosine-phosphorylated pax- nents and adhesive properties by mitogens and chemo-
illin or another adaptor protein, p130Cas, and can then use attractants, for example, is essential for the rapid dissolu-
its SH3 domain to recruit multiple additional proteins. tion of preexisting adhesions and the establishment of new
These include the GEF DOCK180, which activates the small contact sites during cell migration.
GTPase Rac1 (Miranti and Brugge 2002; Legate et al. 2009).
The Rac/Cdc42-GEF a-Pix is also activated upon integrin
4.2 Signaling by Cell Adhesion Molecules (CAMs)
ligation by binding to phosphorylated paxillin and by the
local accumulation of PIP3. Moreover, Src or FAK can phos- The formation of adhesive structures between adjacent
phorylate and activate Vav, a Rac GEF that is recruited to the cells, including adherens junctions and tight junctions,
newly formed adhesive structures (Miranti and Brugge contributes to the establishment of cell polarity, differenti-
2002; Legate et al. 2009). This results in the rapid remodel- ation, and survival and consequently key morphogenetic
ing of the actin cytoskeleton by Rho GTPases and their processes involved in embryonic development, control of
downstream effectors and the relay of the signals to the tissue homeostasis, and tissue repair in adults. A large fam-
nucleus by JNK and p38 (Miyamoto et al. 1995; Miranti ily of cell adhesion molecules (CAMs) provides mechanical
and Brugge 2002; Morrison 2012). adhesion among cells, while initiating signaling via net-
The assembled protein network thus both contributes works that control cellular behavior in response to the
to adhesion to the ECM and other surrounding cells and microenvironment. In general, cadherin molecules medi-
orchestrates signaling events that enable the cells to respond ate cell–cell adhesion at adherens junctions, claudins con-

C.-H. Heldin et al.
tribute to the formation of tight junctions, and immuno- tumor cells (Vleminckx et al. 1991; Thiery and Sleeman
globulin-like CAMs (Ig-CAMs) accumulate throughout 2006). However, the engagement of cadherins in newly
the intercellular boundary (Cavallaro and Dejana 2011). formed cell contacts promotes cell proliferation and sur-
Other CAMs, known as nectins, can participate in both vival through the activation of MAPKs, PI3K, and Rho
adherens and tight junctions (Takai et al. 2008). GTPases (Pece et al. 1999; Pece and Gutkind 2000; Braga
The cadherins are calcium-dependent, homophilic, and Yap 2005). This process often involves the engagement
cell–cell adhesion molecules expressed in nearly all cells of growth factor receptors such as EGFR, VEGFR2, FGFR,
in solid tissues. These molecules participate in cell–cell and PDGFR, promoting their ligand-independent cluster-
recognition, and only cells expressing the same type of ing and activation and prolonging the activation by ligands
cadherins may adhere to each other (Nose et al. 1988). by enhancing receptor recycling and limiting their degra-
The “classical” cadherins were originally named based on dation (Carmeliet et al. 1999; Pece and Gutkind 2000;
the tissue in which they are most prominently expressed, Suyama et al. 2002; Cavallaro and Dejana 2011).
for example, E-cadherin in epithelial cells, VE-cadherin in Cadherins can also control multiple cellular processes
vascular endothelial cells, and N-cadherin in nervous sys- by associating with Src-family kinases, G proteins of the
tem and mesenchymal cells (Gumbiner 2005). These cad- Ga12/13 family, and phosphatases, such as density-en-
herins are single-pass transmembrane proteins that form a hanced phosphatase (RPTPh), the tyrosine phosphatase
core adhesion complex in which a cadherin dimer binds SHP2, and vascular endothelial protein tyrosine phospha-
through its extracellular region to another cadherin dimer tase (VE-PTP) (Cavallaro and Dejana 2011). Cadherins
on an adjacent cell in a calcium-dependent manner. The thus contribute to cell–cell recognition and adhesion while
cadherin intracellular region is anchored in the plasma promoting cell survival and restricting cell motility/growth
membrane and linked to the cytoskeleton through a family by regulating intracellular signaling at the plasma mem-
of proteins known as catenins (Gumbiner 2005). b-Cate- brane. In some cases, the cadherin intracytoplasmic tail
nin interacts with the distal part of the cadherin cytoplas- can translocate to the nucleus and regulate transcription
mic tail, and p120 catenin interacts with a more proximal after shedding of the ectodomain by cell-surface matrix and
region (Gumbiner 2005). a-Catenin binds primarily to disintegrin family proteases and cleavage of the carboxy-
cadherin-associated b-catenin and provides a physical terminal tail by intracellular proteases, such as g-secretase
link to the actin cytoskeleton, by binding actin filaments (Cavallaro and Dejana 2011), which is reminiscent of
either directly or indirectly through other actin-binding Notch signaling.
proteins, such as vinculin, a-actinin, and formins (Kobie- Tight junctions involve numerous adhesion molecules,
lak and Fuchs 2004; Mege et al. 2006). p120 regulates cell including occludin, junctional adhesion molecules
movement through its ability to control both cell adhesion (JAMs), and the claudin family of tetraspan transmem-
by governing the availability of cadherins at the plasma brane proteins, as well as intracellular adaptors, such as
membrane and actin cytoskeleton organization by regulat- ZO1 and ZO2 (Tsukita et al. 2001). Claudins are the major
ing Rho GTPases (Anastasiadis and Reynolds 2001; Grosh- adhesive proteins at tight junctions; whether they play a
eva et al. 2001; Yanagisawa and Anastasiadis 2006). p120 direct role in cell signaling is not clear yet.
can also directly affect gene expression by repressing tran- Ig-CAMs are cell-surface glycoproteins that accumulate
scription by scaffolding a nuclear complex including the at the cell–cell boundary, and their homophilic interac-
gene silencer Kaiso (Daniel and Reynolds 1999). tions contribute to cell–cell recognition and adhesion in
The formation of cadherin-dependent adhesions con- a calcium-independent fashion (Loers and Schachner
tributes to growth inhibition upon cell–cell contact. This 2007; Cavallaro and Dejana 2011). Although most Ig-
has often been associated with inhibition of the canonical CAMs have a transmembrane region and a cytoplasmic
Wnt pathway by cadherins, which retain b-catenin at the tail, some associate with the cell surface via a GPI anchor.
plasma membrane and therefore limit the pool of free b- In the former case, the cytoplasmic tail of Ig-CAMs can
catenin available for nuclear signaling (Nelson and Nusse interact with cytoskeletal proteins such as actin, ankyrins,
2004). Recent evidence suggests that cadherin engagement and spectrin and can also initiate signal transduction (Ca-
can also activate the Hippo pathway, which results in the vallaro and Dejana 2011). For example, the formation of
cytoplasmic retention of the transcriptional coactivator NCAM-based adhesions results in the activation of a kinase
YAP that is necessary for cell growth (Kim et al. 2011). In cascade including CaMKIIa, the Src-family kinase Fyn,
epithelial cells, E-cadherin acts as a tumor and metastasis and FAK, and this promotes neurite outgrowth and neu-
suppressor. Its expression and function are down-regulated ronal survival (Bodrikov et al. 2008). NCAM also stimu-
or altered in many human cancers, and its reexpression lates PKCbII by recruiting it to the membrane through
decreases both the proliferative and invasive capacity of the formation of a signalling complex involving a protein

known as growth-associated protein 43 (GAP43) (Korshu- their cognate ligands, in the most simplistic scenario, either
nova and Mosevitsky 2010). In common with cadherins, changes the cellular localization of the NR or its interaction
NCAM can interact with multiple growth factor receptors, with repressive and activating cofactors in the nucleus.
including FGFR, regulating their signaling capacity. What distinguishes NRs from other genres of receptors is
Signaling by CAMs—either direct or indirect actions the ability to mediate transcription without intermediate
engaging and prolonging the activity of RTKs—is likely to signaling cascades. Instead, they directly bind to target
play a key role during the formation of cell–cell contacts, genes. Nuclear–cytoplasmic cycling of some NRs allows
particularly during embryonic development, morphogen- them to have nongenomic effects and also to be targets of
esis, and tissue repair (Pece and Gutkind 2000; Dumstrei cytoplasmic signaling cascades (Wehling 1997).
et al. 2002; Andl et al. 2003; Fedor-Chaiken et al. 2003). This
may accelerate the growth rate without the need for elevated
5.1 Structure and Mechanisms of Receptor
local levels of growth factors. The stabilization of cell–cell
Activation
contacts may subsequently reduce signaling by ligand-acti-
vated RTKs by sequestering them in CAM-containing clus- Nuclear receptors generally contain five functional do-
ters, while favoring their ligand-independent activation of mains. The A/B region at the amino terminus is divergent
survival pathways, such as PI3K–Akt signaling (Pece and and in some NRs contains a ligand-independent transcrip-
Gutkind 2000; Qian et al. 2004). Concomitantly, CAMs may tional activation function domain (AF1). The highly con-
restrict cell and organ overgrowth by limiting the availabil- served DNA-binding domain (DBD) is located in the
ity of free b-catenin and YAP (Nelson and Nusse 2004; Kim central C domain. The carboxyl terminus is the E region,
et al. 2011). In these cases, CAMs may help prevent tumor which contains the ligand-binding domain (LBD). A flex-
formation while generating survival and differentiation sig- ible hinge D region links the DBD and LBD (Fig. 10). The
nals. The microenvironment and RTK signaling networks DBD contains tetracysteine (C4) zinc fingers that are
can, in turn, modulate the localization, expression, and unique to NRs and define membership in the superfamily.
stability of CAMs and the proteins that they associate The DBD typically targets the NR to a specific DNA element
with, thus regulating their adhesive properties and signaling termed a hormone-response element (HRE). The LBD is
capacity. Conversely, CAMs can regulate RTK signaling, composed of 12 a helices and mediates ligand recognition,
acting as rheostats governing the intensity and duration of dimerization, interaction with coactivators/corepressors,
their signals in response to environmental cues such as cell and ligand-dependent transcriptional activation. The last
density, tissue architecture, and polarity. helix, helix 12, within the LBD is the AF2 domain, which
enables NRs to interact with short LxxLL motifs in coacti-
vators or corepressors. These are termed the NR box or
5 NUCLEAR RECEPTORS
CoRNR box, respectively (Hu and Lazar 1999). Whereas
Nuclear receptors (NRs) comprise a large superfamily of AF1 domains vary greatly among all NRs and have a pro-
intracellular transcription factors that can effect gene ex- pensity to stay disordered, AF2 domains have similar struc-
pression changes in response to a wide variety of lipophilic tures (Warnmark et al. 2003).
ligands (Sever and Glass 2013). In this respect, they differ
from most other receptors in that they do not reside in the
5.2 Nuclear Receptor Classification
plasma membrane, which many of their ligands can cross.
Typical NR ligands include steroids, vitamins, dietary lip- NRs can be classified based on their DNA-binding mech-
ids, cholesterol metabolites, and xenobiotics. Ligands for anism (Fig. 10) or their ligand (Table 2). On the basis of
24 NRs have been identified; the remaining family mem- their mode of actions, nuclear receptors are classified into
bers are considered orphan receptors (Mangelsdorf et al. four types. Type I and type III NRs are normally seques-
1995). There are 48 NRs in humans (49 in mice and 18 in tered in the cytoplasm by heat shock proteins. Ligand bind-
Drosophila). NRs are believed to be only one of two tran- ing to type I NRs dissociates heat shock proteins and results
scription factor families that are metazoan specific (King- in nuclear enrichment. Type I NRs bind to DNA as homo-
Jones et al. 2005; Degnan et al. 2009). Because many are dimers, and the response elements they recognize are in-
endocrine hormone receptors, this suggests a potentially verted repeats. Type II receptors, unlike type I receptors, are
critical role in the evolution of animal physiology. Hor- normally enriched in the nucleus and are bound to DNA
monal NRs are typically classified by the type of ligands even in the absence of ligand. They generally bind to DNA
to which they bind, whereas orphans have various different as heterodimers with the retinoid X receptor (RXR). In the
abbreviations, indicating, for example, similarity to known absence of ligand, type II receptors repress transcription via
receptors (e.g., estrogen-related receptor, ERR). Binding of association with corepressors. In the presence of ligand,

C.-H. Heldin et al.
A A/B C D E
AF1 DBD LBD
Zn2+ Zn2+ Hinge AF2
Nx Nx
Palindromes Direct repeats Half sites
Homodimers Homo/heterodimers Monomers

(steroid receptors) (VDR-RXR, RXR-RXR, (ERRs, REV-ERBs,
PPAR-RXR, RAR-RXR, RORs, etc.)
TR-RXR, etc.)
Type I Type II/III Type IV
Figure 10. General structure and binding of nuclear receptors. (A) Domain organization of a typical nuclear
receptor. (B) Three modes of signal transduction: as monomers, heterodimers, and homodimers. (From Sonoda
et al. 2008: modified, with permission, # Elsevier.)
corepressors are dissociated, and coactivators including element, ERE). These sequences can mediate either activa-
histone-modifying enzymes are recruited by the type II tion or repression in response to hormone. The DBDs of
receptors for gene activation. Examples of type II receptors steroid receptors are highly similar. Thus, the glucocorti-
include the thyroid hormone receptor (TR) and retinoic coid receptor (GR), the mineralocorticoid receptor (MR),
acid receptor (RAR). Type IV receptors bind as monomers the androgen receptor (AR), and the progesterone receptor
and recognize half-site response elements. (PR) all bind to overlapping response elements. Type III
receptors are similar to type I receptors except that they
5.3 Three Modes of Binding to Promoter Regions recognize direct repeats instead of inverted repeats.
Influence Transcription
5.3.2 Heterodimers
Hormone-responsive NRs are sequestered in the cytoplasm
or are bound to HREs in repressive complexes that include RXR forms heterodimers with various nonsteroidal mem-
chromatin modifiers such as histone deacetylases (HDACs), bers of the NR superfamily that do not bind to HREs effi-
nuclear corepressors (N-CoRs), and SMRT proteins (for ciently by themselves. Depending on the type of NR, HREs
“silencing mediator of retinoid and thyroid receptors”) have specific conformations. Unlike the type I receptors
(Perissi et al. 2010). Ligand binding typically promotes nu- mentioned above, type II receptors form retinoid-acid-
clear translocation and/or recruitment of coactivators that related-receptor (RXR)-containing heterodimers that rec-
displace corepressors to initiate transcription (Rosenfeld ognize direct repeats of AGGTCA or similar sequences
et al. 2006). Coactivators that mediate NR function include separated by specific spacing (Umesono et al. 1991). The
PGC1, SIRT1, p160, and p300 proteins (Sonoda et al. 2008). RAR- and peroxisome proliferator-activated-receptor-g
Mechanistically, NRs can mediate transcription (either re- (PPARg)-containing dimers RAR–RXR and PPARg-RXR
pression or activation) in the following manner. bind to a direct repeat (DR-1), whereas the vitamin D3 re-
ceptor (VDR)-, TR-, and RAR-containing dimers VDR–
5.3.1 Homodimers RXR, TR–RXR, and RAR–RXR bind to DR-3, DR-4, and
DR-5, respectively (Evans 2005).
Type I and type III receptors bind to DNA as homodimers
when bound to their cognate ligands. Type I receptors in-
5.3.3 Monomers
clude all steroid receptors, and their response elements
typically consist of two hexameric inverted ( palindromic) Type IV NRs bind to just one AGGTCA site as monomers
repeat half-sites, for example, AGAACA (the glucocorticoid in a ligand-independent manner. These receptors use an
response element, GRE) or AGAACA (the estrogen response extended DBD. There are currently three known types of

Table 2. The nuclear receptor superfamily 6.2 Nonsteroidal Hormonal Receptors

Steroid receptors Instead of acting as homodimers, all nonsteroidal hormone
GR Glucococorticoid
receptors, including TR, use RXR as a partner to form het-
MR Mineralocorticoid
AR Androgens erodimers. VDR and RAR are activated by calcitriol (vita-
PR Progesterone min D) and retinoic acid. RXR is conserved in invertebrates
TRa, TRb Thyroid hormone and may be an ancient member of the NR family. RXRs (a,
ERa, ERb Estrogen b, and g) are activated by the novel retinoid isomer 9-cis
Vitamin receptors retinoic acid and other synthetic agents (rexinoids) (Man-
VDR Vitamin D gelsdorf et al. 1992). RXR forms three different types of
RARa, RARb, RARg Retinoic acid dimers. Other than the nonpermissive heterodimers men-
Fatty acids and derivatives tioned above (e.g., RAR and VDR), which cannot be acti-
PPARa, PPARb/d, PPARg Fatty acids vated by the RXR ligand, RXR can form homodimers and
LXRa, LXRb Oxysterol permissive heterodimers (e.g., with PPAR and liver X recep-
FXR Bile acids tor, LXR) that can be activated by RXR-ligand binding.
RXRa, RXRb, RXRg Rexinoids
Xenobiotic receptors
CAR Androstane metabolites
6.3 Receptors for Fatty Acids and Derivatives
PXR Pregnane derivatives The PPAR subfamily includes PPARa, PPARd, and PPARg.
Adopted orphan receptors Each of the PPARs binds to common response elements as
HNF4a, HNF4g Fatty acids heterodimers with RXR, using fatty acid ligands, which
REV-ERBa, REV-ERBb Heme function as metabolic sensors. PPARa is highly expressed
RORa, RORb, RORg Cholesterol, retinoic acid in the liver and is the target of the fibrate class of drugs used
SF1, LRH1 Phosphatidylinositols
to control hyperlipidemia (Issemann and Green 1990).
ERRa, ERRb, ERRg Estrogen
PPARd is universally expressed and promotes fatty-acid ox-
Orphan receptors
idation. PPARg is required for adipogenesis, promotes fat
SHP
DAX1
storage, and has been widely studied for its role in the me-
TLX tabolic syndrome (Barak et al. 1999). LXRa and LXRb and
PNR farnesoid X receptor (FXR) are sensors for cholesterol me-
GCNF tabolites such as oxysterols and bile acids, respectively. Both
TR2, 4 LXRs and FXR form heterodimers with RXR. LXRs are
NR4A1, NR4A2, NR4A3 important for maintaining cholesterol homeostasis, where-
COUP-TFa, COUP-TFb, COUP-TFg as FXR acts as the primary bile acid sensor by repressing
expression of 7a-hydroxylase (CYP7A1), the rate-limiting
enzyme in bile acid production, through up-regulation of
monomer-binding receptors, which are defined by unique
two orphan NRs, SHP and LRH1, upon bile acid stimula-
sequences 5′ to the consensus site. REV-ERBs tend to bind
tion (Lu et al. 2001). SHP and LRH1 form inactivating
to A(A/T)CTAGGTCA sequences, whereas ERRs bind to
heterodimers to repress transcription of CYP7A1, thus
TNAAGGTCA sequences.
turning off bile acid production.
6 FUNCTIONS OF NUCLEAR RECEPTORS

6.4 Xenobiotic Receptors
6.1 Steroid and Thyroid Hormone Receptors
The xenobiotic receptors include the constitutive active/
Steroid and thyroid receptors maintain homeostasis by androstane receptor (CAR) and pregnane X receptor
acting as sensors for circulating hormones from the adre- (PXR). Both CAR and PXR form heterodimers with RXR
nals, ovaries, testes, and thyroid. GR, MR, AR, and PR are and bind promiscuously to different response elements
closely related and bind common DNA sequences. Follow- (Lehmann et al. 1998; Sueyoshi et al. 1999). Their role is
ing ligand treatment, these receptors translocate from to induce expression of enzymes such as CYP3A that pro-
the cytoplasm to the nucleus and bind to palindromes of mote the metabolism of exogenous compounds (xenobi-
the GR half-site AGAACA as homodimers. All other mem- otics). Unlike typical NRs, PXR has a promiscuous LBD
bers of the superfamily, including ER and TR, bind to pocket that binds a wide variety of natural and synthetic
response elements that contain variations of the ER half- compounds. Activation of xenobiotic receptors is not al-
site AGGTCA. ways beneficial to the host. For example, upon exposure to

C.-H. Heldin et al.
high doses of acetaminophen (a common component of survival. Like steroids, gases are able to cross the plasma
pain killers and cocaine), CAR can mediate production of membrane and bind to intracellular targets. Signal trans-
toxic by-products through up-regulation of three CYP en- duction via gases is predominantly mediated by heme-con-
zymes that lead to acute hepatotoxicity (Zhang et al. 2002). taining proteins. Binding of the gas to the sensor proteins
via the heme moiety can affect their activity or stability. In
the case of oxygen, the source of the gas is the environment.
6.5 Adopted Orphan Receptors
In contrast, nitric oxide and carbon monoxide can be gen-
Discovery of natural or synthetic ligands for several orphan erated in neighboring cells and function as bona fide para-
NRs has led to their classification as “adopted” orphan crine signals (through covalent and noncovalent binding).
receptors (e.g., REV-ERBa and REV-ERBb). REV-ERBs
are repressors that compete with retinoid-related orphan
7.1 Signal Transduction via Oxygen
receptors (RORa, RORb, and RORg) for binding to (A/
T)6RGGTCA HREs (Forman et al. 1994). The REV-ERB Levels of oxygen inside mammalian cells are mainly detect-
ligand is neither a lipid nor a hormone but, rather, a single ed by hypoxia-inducible factor (HIF) (Wang et al. 1995).
heme molecule (Reinking et al. 2005). Many heme-con- HIF is a heterodimer comprising a regulatory a subunit and
taining proteins also bind to diatomic gases, and REV- a DNA-binding b subunit. At high oxygen levels, the HIFa
ERBs are also responsive to NO and CO (see below). subunit is hydroxylated by prolyl hydroxylase domain
RORs are proposed to bind cholesterol and retinoid acid, (PHD) proteins and targeted for proteosomal degradation
although whether this is important in antagonizing REV- by interacting with the von Hippel –Lindau (VHL) protein,
ERBs is not clear (Kallen et al. 2002; Stehlin-Gaon et al. which is the targeting subunit of a cullin RING ligase (CRL)
2003). NR5A subfamily members SF1 (NR5A1) and LRH1 2 E3 ubiquitin ligase. The PHD proteins are dioxygenases
(NR5A2) were originally thought to be constitutively ac- that catalyze the incorporation of both atoms of molecular
tive. Recent analysis, however, reveals that these receptors oxygen into their substrates. At low oxygen levels, HIFa
can bind to phosphatidylinositols, including PIP2 and PIP3 degradation is inhibited and HIFa accumulates inside the
(Newton et al. 2014). They may therefore link transcription cell. It associates with HIFb, which binds to DNA elements
and phospholipid signaling (Krylova et al. 2005). termed hypoxia responsive elements (HREs) that have the
core sequence RCGTG. HIF targets include erythropoietin,
which stimulates red blood cell production; vascular endo-
6.6 True Orphan Receptors
thelial factor (VEGF), which stimulates angiogenesis
True orphans are constitutive activators or repressors that (growth of new blood vessels); and other enzymes in rele-
do not bind ligands. The NUR subfamily (NR4A1, NR4A2, vant pathways, including glycolytic enzymes.
and NR4A3) binds to DNA as monomers, homodimers,
and heterodimers with RXR (or another NUR). NURs have
7.2 Signal Transduction via Nitric Oxide
no known ligands, and their activity is controlled by their
expression levels. ERRa, ERRb, and ERRg interfere with Nitric oxide (NO) was first discovered as an endothelial-
ER and AR signaling. ERRs are activated by coactivators derived relaxing factor (EDRF) and subsequently found to
such as PGC1a, an important metabolic regulator (Hardie be a powerful mediator in other biological processes, includ-
2012). Germ-cell nuclear receptor (GCNF) is an unusual ing platelet aggregation, synaptic transmission, and inflam-
member of the NR superfamily that binds to a DR-0 motif matory responses (Moncada et al. 1991). Vascular NO is a
and may function as a transcriptional repressor in stem cells key regulator of endothelial function and stimulates blood
(Fuhrmann et al. 2001). vessel dilation, prevents platelet aggregation and adhesion,
NRs thus represent an important metazoan strategy for and inhibits proliferation of vascular smooth muscle cells.
regulating gene expression programs by integrating differ- NO is produced by NO synthase (NOS) from the amino acid
ent intracellular and extracellular signals. Moreover, cross- L-arginine and detected by the heme-containing enzyme
talk between NRs and other signal transduction pathways soluble guanylyl cyclase (sGC). Synthesis of NO from argi-
adds an additional layer of complexity to their already di- nine involves two mono-oxygenation steps and requires one
verse functions. O2, one NADPH, and tetrahydrobiopterin (BH4).
The electronic structure of NO makes it an excellent
ligand for heme, allowing it to bind to sGC heme at a low
7 GASES
and nontoxic concentration. sGC is a heterodimer com-
The ability to sense and adapt to changes in levels of dia- posed of a1 and b1 subunits. H105 in the b1 amino ter-
tomic gases (O2, NO, and CO) is crucial for an organism’s minus is the heme ligand (Wedel et al. 1994). In a two-step

process, NO first binds to the sGC heme moiety, forming a types of ligands, including proteins, peptides, and certain
6-coordinate complex. In the second step, the heme- lipids, that bind to receptors at the cell surface, and steroids
H105 bound breaks forming a 5-coordinate complex. and gases that can pass across the plasma membrane and
The second step triggers a conformational change in the bind to intracellular receptors. Recent work has provided
sGC catalytic domain, leading to its activation. When ac- immense insights into how receptors are activated after
tivated by NO, sGC converts GTP to cGMP, which then acts ligand binding, how they initiate signaling inside the cell,
as a second messenger (Newton et al. 2014). Besides sGC, and how signaling is terminated. A striking feature is that
NO can also interact with other heme-containing enzymes, regulated dimerization or oligomerization is involved in
including methionine synthase, cytochrome c oxidase, cy- the control of many plasma membrane receptors and in-
tochrome P450, hemoglobin, and ferritin (Moncada and tracellular signaling molecules. Moreover, signal transduc-
Palmer 1991; Brown and Cooper 1994; Danishpajooh et al. tion often occurs by the reversible formation of complexes
2001). REV-ERBa and REV-ERBb have also been shown to and specific translocations of signaling molecules, rather
be able to bind NO through their heme-containing LBDs, than by random diffusion events. Another striking feature
which results in inhibition of the ability of REV-ERB to is that many different types of posttranslational modifi-
repress transcription (Pardee et al. 2009). cations of proteins are involved in the regulation of the
In S-nitrosylation, NO covalently links to the thiol side activity, stability, and subcellular localization of signaling
chain of cysteine residues in target proteins and modifies molecules. Furthermore, different signaling inputs con-
their activities. An example of NO-mediated S-nitrosyla- verge on a few well-conserved intracellular pathways, sev-
tion is the modification of b-catenin in the adherens junc- eral of which link to transcriptional regulation of gene
tion to increase endothelial permeability (Thibeault et al. programs.
2010). Whereas the initial phase of signal transduction often
involves amplification mechanisms, such as inhibition of
phosphatases in conjunction with activation of tyrosine
7.3 Signal Transduction via Carbon Monoxide
kinases, subsequent phases contain different negative feed-
Endogenous carbon monoxide is generated by heme oxygen- back and termination mechanisms, acting at many differ-
ase (HO), an enzyme that degrades heme into iron, biliver- ent levels. There is also extensive crosstalk between different
din, and CO in aging red blood cells and is induced by many signaling pathways. An important question that remains
cellular stressors and toxins, including UV, hydrogen perox- to be answered is exactly how specificity of signaling is
ide, heavy metals, and arsinite. Like NO, CO has affinity for achieved. Moreover, most of our knowledge about receptor
heme-containing proteins and activates sGC by binding to its signal transduction mechanisms comes from studies of
heme motif, which stimulates similar biological processes, cultured cells; much more work is needed before we under-
including intestinal smooth muscle relaxation and neural stand signal transduction at the organismal level.
transmission (Rodgers 1999). In olfactory neurons, CO acts
as a neurotransmitter via sGC to produce cGMPs (Verma
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Carl-Henrik Heldin, Benson Lu, Ron Evans and J. Silvio Gutkind
Cold Spring Harb Perspect Biol 2016; doi: 10.1101/cshperspect.a005900
Subject Collection Signal Transduction
Signals and Receptors Synaptic Signaling in Learning and Memory

Carl-Henrik Heldin, Benson Lu, Ron Evans, et al. Mary B. Kennedy
Cell Death Signaling Vertebrate Reproduction
Douglas R. Green and Fabien Llambi Sally Kornbluth and Rafael Fissore
Signaling Networks that Regulate Cell Migration Signaling in Lymphocyte Activation
Peter Devreotes and Alan Rick Horwitz Doreen Cantrell
Signaling Networks: Information Flow, Signaling in Muscle Contraction
Computation, and Decision Making Ivana Y. Kuo and Barbara E. Ehrlich
Evren U. Azeloglu and Ravi Iyengar
Signal Transduction: From the Atomic Age to the Toll-Like Receptor Signaling
Post-Genomic Era Kian-Huat Lim and Louis M. Staudt
Jeremy Thorner, Tony Hunter, Lewis C. Cantley, et
al.
Signaling by the TGFβ Superfamily Signaling Pathways that Regulate Cell Division
Jeffrey L. Wrana Nicholas Rhind and Paul Russell
Subversion of Cell Signaling by Pathogens Signaling Mechanisms Controlling Cell Fate and
Neal M. Alto and Kim Orth Embryonic Patterning
Norbert Perrimon, Chrysoula Pitsouli and Ben-Zion
Shilo
Signaling by Nuclear Receptors Signaling Pathways that Control Cell Proliferation
Richard Sever and Christopher K. Glass Robert J. Duronio and Yue Xiong
For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/
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Signals and Receptors

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Signals and Receptors

Communication between cells in a multicellular organism occurs by the production of ligands

1 Introduction 6 Functions of nuclear receptors

1 INTRODUCTION immune system and also promote cell differentiation. Cy-

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Tyrosine L Cysteine- Fibronectin Leucine- Cadherin Discoidin Ig EGF-like Kringle

SAM Psi WIF Ephrin Fz Ldla YMTD Acid Sema Mam

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EPOR βC IL6Rα Gp130 LIFR Interferon receptors

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metric complex containing one ligand and two receptors heparin DI

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ATP Rac/ Ras

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TNFR1 221 TNFα

TNFR2 174 TNFβ

Fas 145 FasL

DR3 193 VEGI

DR4 203 TRAIL

EDAR 236 EDA-A1

NGFR 155 NGF

RANK 282 RANKL

LTβR 187 LTα/LTβ

CD30 188 CD30

BCMA 106 APRIL

XEDAR 134 EDA-A2

TNF homology region

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out signaling (Legate and Fassler 2009; Moser et al. 2009).

Table 1. Ligands for a– b integrin heterodimers

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Outside-in Integrin RTK

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AF1 DBD LBD

Zn2+ Zn2+ Hinge AF2

Palindromes Direct repeats Half sites

Homodimers Homo/heterodimers Monomers

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Table 2. The nuclear receptor superfamily 6.2 Nonsteroidal Hormonal Receptors

6 FUNCTIONS OF NUCLEAR RECEPTORS

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Signals and Receptors

Cold Spring Harb Perspect Biol 2016; doi: 10.1101/cshperspect.a005900

Subject Collection Signal Transduction

Signals and Receptors Synaptic Signaling in Learning and Memory

For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

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