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Cell Surface Receptors

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 2.06 Cell Surface Receptors
N Popovic and E Wilson, Texas A&M Health Science Center, College of Medicine, College Station, TX, USA
2010 Elsevier Ltd. All rights reserved.

2.06.1 Introduction 81
2.06.2 General Characteristics of Cell Surface Receptors 82
2.06.3 G-Protein Coupled Receptors 83
2.06.3.1 Overview and General Characteristics 83
2.06.3.2 Pathologies Associated with G-Protein Coupled Signaling 86
2.06.4 Enzyme-Linked Receptors 86
2.06.4.1 Receptor Tyrosine Kinases 87
2.06.4.2 Transforming Growth Factor- Receptors 88
2.06.4.3 Ligand-Gated or Receptor-Operated Ion Channels 88
2.06.5 Adhesion Molecules: Mediators of CellMatrix and CellCell Interactions 88
2.06.5.1 Integrins 89
2.06.5.2 Cadherins 90
2.06.5.3 Selectins and Ig CAM Adhesion Molecules 90
2.06.6 Conclusions 90
References 90

Abbreviations GRK G-protein receptor kinase

BARK ~
-adrenergic receptor kinase GTP guanine nucleotide triphosphate
BMP morphogenetic protein IGF insulin-like growth factor
CAM cell adhesion molecule MAPK mitogen-activated protein kinase
ECM extracellular matrix protein NGF nerve growth factor
EGF epidermal growth factor PDGF platelet-derived growth factor
FAK focal adhesion kinase PI 3-kinase phosphatidyl inositol 3-kinase
FGF fibroblast growth factor PLC phospholipase
GABA -aminobutyric acid A RTK receptor tyrosine kinase
GAP GTPase activating protein SH2 src-homology domain 2
GDP guanine nucleotide diphosphate SOS son-of-sevenless
GEF guanine nucleotide exchange factor TGF transforming growth factor
GPCR G-protein coupled receptor VEGF vascular endothelial growth factor

2.06.1 Introduction
Cells are able to respond to changes in the environ-
ment by the interaction of external stimuli with cell-
associated receptors which in turn activate signal
transduction pathways that serve to regulate the cel-
lular response to the change in environmental
conditions. While cells do contain some intracellular
receptors (e.g., steroid hormone receptors), the vast
majority of the cellular stimuli cannot cross the
plasma membrane. This limitation necessitates that,
for the cell to interact and respond to changes in
external stimuli, there are receptors that are integral
plasma membrane proteins and are thus able to inter-
act with stimuli in the extracellular milieu and then
initiate intracellular signaling events that regulate
changes in cell behavior. This chapter will focus on
the membrane spanning receptors and these recep-
tors will be referred to as cell surface receptors for
the general class of receptors.
Figure 1 illustrates the general relationship
between external stimuli, cell surface receptors,
intracellular signaling cascades, and altered cellular
responses. The external stimuli that initiate these

81
82 Receptor Systems
External stimuli
Cell surface receptors
Signal transduction
Effector
Messenger
molecules
Cell behavior
Contraction / Growth /
Differentiation
Relaxation
Secretion Metabolism
Figure 1 Schematic representing central role of the cell
surface receptors in recognizing external stimuli and
activation of cellular transduction pathways leading to
changes in cellular behavior. Illustrated are external stimuli,
cell surface receptors, signal transductions, and their
relationship to changes in cellular activities.
process are of many and varied types of molecules
including hormones, cytokines, neurotransmitters,
growth factors, and extracellular matrix molecules
and fragments. Interaction of these varied external
stimuli leads to both short-term cellular changes
including shape changes, secretion, contraction/
relaxation, changes in metabolism, and migration to
name a few events, as well as long-term adaptations
including changes in gene expression, proliferation,
differentiation, and even cell death or apoptosis. The
types of molecules that initiate these responses and
interact with the cell surface receptors range from
ions, small compounds, peptides, and proteins to
physical forces such as vibration, pressure, flow, and
light. The varied nature of the stimuli that a cell
needs to respond to requires a large number and
varied types of cell surface receptors that can bind
these stimuli and initiate a wide range of signaling
pathways that can lead to specific downstream
responses. One commonality among the various
receptor systems is that they all amplify the signal
from one receptor ligand interaction to a more long-
term signaling event. In this chapter we will focus on
four classes of cell surface receptors: the G-protein
couple receptors, the tyrosine kinase receptors, other
enzyme-linked receptors, and adhesion molecules
(Alberts et al. 2007).
2.06.2 General Characteristics
of Cell Surface Receptors
The concept of receptors was first introduced in the
context of the mechanisms of action of drugs, and the
term was used long before the molecular nature of
the various receptors was known. The primary func-
tion of physiological receptors is to bind the
appropriate ligand on the external surface of the
cell and to propagate the regulatory signal in the
target cell. Thus, all receptors are considered to
have a ligand-binding domain and an effector
domain. The receptors then serve to integrate the
signals from the external stimuli to coordinate cellu-
lar responses. These properties make the receptor
systems excellent targets for drugs and also the sites
of action for many chemical toxicants.
Three key considerations are often used to clas-
sify the nature of the interaction of a stimulus (e.g.,
drugs, toxicants, and hormone growth factors) with
its receptor. First, receptors determine the quantita-
tive relationship between the amount (dose) of the
stimulus and the physiologic effect. This relationship
is determined by the affinity of the stimulus for the
receptor and the total number of receptors present on
the cell surface. Second, receptors are responsible for
the selectivity of the interaction of a stimulus with
the cells service. Selectivity is determined by the
molecular nature of the ligandreceptor interaction.
Finally, receptor interaction and structure lead to the
ability to have both agonists (activators) and antago-
nists (inhibitors), which contributes to their
importance in the fields of pharmacology, drug
development, and toxicology.
The use of radiolabeled ligands allowed for the
characterization of receptors before the molecular
characteristics of the proteins were known. The use
of such experimental systems showed that ligand
receptor interactions could be treated like association
interactions between two molecules and that an affi-
nity could be determined. These types of studies also
showed that there were a limiting number of recep-
tors for the ligand and that there were saturation

kinetics. The concept of multiple receptors for the
same ligand was determined by the shape of the
binding curves. These processes have been discussed
in detail in other texts including Bourne and von
Zastrow (2007) and Brunton et al. (2007). We will
focus on the description of the primary types of
receptors and their role in human pathologies and
as targets for toxicants.
2.06.3 G-Protein Coupled Receptors
2.06.3.1 Overview and General
Characteristics
The largest family of cell surface receptors is that of
the guanine nucleotidebinding protein or G-protein
coupled receptors (GPCR), which are also known as
seven-transmembrane receptors because of this com-
mon structural feature. Approximately 800 human
genes code for receptors in this family, which interact
with ligands as diverse as ions, hormones, neurotrans-
mitters, and other sensory stimuli. This family of
receptors is the target for approximately 30% of the
drugs on the market (Hopkins and Groom 2002).
These facts indicate the importance of this class of
receptors in both normal physiology and in human
disease of the G-protein coupled receptors and as
potential targets for toxicants.
This family shares common structural features
including the characteristic seven-membrane traver-
sing segments, external loops of the membrane-
spanning region and the N-terminal region that form
the ligand-binding domain, and the cytosolic loops and
C-terminal tail that form regions that are involved in
interaction with the guanine nucleotide-binding pro-
teins (G proteins) and regulation by other intercellular
proteins (Figure 2) (Pierce et al. 2002). This common
structure allows for the approximately 800 different
receptors to interact with the wide array of extracel-
lular ligands that they bind with both specificity and
selectivity and to initiate a number of diverse signaling
pathways by interacting with different G proteins that
regulate specific signaling pathways.
Guanine nucleotidebinding proteins or G pro-
teins are heterotrimeric proteins that are composed
of , , and subunits. The subunit contains the status of the receptor (to be discussed in more detail
enzymatic activity and plays the primary role in
conveying the signal from the receptor to the effector
molecules. The subunits serve to localize the
G-protein heterotrimer to the membrane through
posttranslational modifications such as myristoyla-
tion (Neer 1995), and can also serve as direct
Cell Surface Receptors 83
activators of signaling events in some cases (e.g.,
potassium channels) (Ford et al. 1998).
The most basic signal transduction pathway of the
GPCR family is that activation of the receptor by
ligand binding results in a conformational change in
the receptor. The resultant change in conformation
allows for the exchange of guanine nucleotide dipho-
sphate (GDP) from the -subunit of the G protein
for guanine nucleotide triphosphate (GTP). This key
step in the process initiates the activation of the
-subunit and its release from the subunits. As
stated above, both the and subunits are capable
of activating effector proteins. Among the G-protein
regulated effector systems are adenyl cyclase, phos-
pholipase C-, and numerous ion channels to name
just a few. Thus, the binding of the external stimuli
results in the amplification of the initial signaling
event into the production of many second messen-
ger molecules leading to the change in cellular
behavior. This series of events is illustrated in
Figure 2 (Bourne 1997).
There are multiple genes encoding each of the
G-protein subunits, which contribute to the diversity
of the overall signaling system. Currently, there are
at least 16 known subunits, 5 distinct subunits,
and 11 subunits in mammals (Luttrell 2006).
Table 1 shows some of the more common G pro-
teins, some of the interacting receptors, and the
associated signaling molecules.
The expression patterns of the various subunit types
vary widely. Some of the subunits, such as Gs, are
expressed ubiquitously and couple multiple receptors
to the stimulation of the same effector systems (e.g.,
adenyl cyclase and cyclic adenyl monophosphate
(cAMP)). Other G subunits, such as transducin,
which couples the GPCR rhodopsin to cyclic GMP
phosphodiesterase are restricted only to specific cell
types, in this case the retinal epithelial cells. Thus,
mutations in specific G proteins or their receptors
may have more widespread physiologic effects or may
be more restricted depending on the expression pattern
of the various components of the system (Luttrell 2006).
The key points in determining how long the
signaling pathway will remain active upon stimulation
include how long the stimulus is present, the activation
later), the length of time that the G protein is in the
GTP bound or active form, thus maintaining the acti-
vated status of the effector system, and the relative half-
life or the second messenger molecules. A number of
other regulatory molecules modulate these various
points. For example, guanine nucleotide exchange
84 Receptor Systems

1
Hormone

Effector
G
G
G

GDP
4 2
Hormone

Effector Effector
G G
G G
G G

GTP GDP GDP GTP

3
Hormone

Effector
G
G
G

5
GTP

Receptor
kinase Second
messenger

P P

Arrestin

Figure 2 Schematic of G-protein coupled receptor activation. (1) Inactive GPCR-G-protein-effector complex poised to
interact with agonist. (2) Agonist binding to receptor induces conformational change in receptor and initiates exchange of
GDP for GTP. (3) G subunit dissociates from subunits and interacts with and activates the effector system leading to
increased second messenger production. (4) GTP hydrolysis leads to inactivation of signaling process and reassociation of
the subunits. (5) Activation of receptor kinases (GRKs) leads to phosphorylation of the receptor and arrestin binding. A
process that results in desensitization of receptor and possible targeting for lysosomal degradation.

factors (GEFs) regulate the exchange of GDP for GTP
upon activation. In the GPCR pathway, the activated
receptor is one of the most prominent GEF. GTPase
activating proteins (GAPs) serve to speed up the cata-
lytic rate of GTP hydrolysis to GDP (Siderovski and
Willard 2005). Misregulation of any of these sites can
cause pathologies (Brunton et al. 2007). Constitutive
activation of certain GPCRs due to subtle mutations
in receptor structure has been shown to give rise to
disease such as retinitis pigmentosa, precocious pub-
erty, and malignant hyperthyroidism (Spiegel and
Weinstein 2004).
It was observed that many agonists became ineffec-
tive after prolonged exposure of the cells or tissues to
them. This process is termed refractoriness, tachyphy-
laxis, or desensitization. This mechanism of action has
been of considerable interest because of the profound
limitation on the efficacy of some drugs and on the
duration of action of certain hormones or stimuli. This
phenomenon has been observed with multiple signal
transduction systems, but has been most studied with
the adrenergic system (Hoffman and Taylor 2001).
Multiple points of regulation of receptor responsive-
ness have been identified including the receptors, G
proteins, adenyl cyclase, and the phosphodiesterase that
hydrolyzes cAMP. How long the receptor is desensi-
tized and the type of desensitization is determined by
which of the components is modified. Heterologous
 Cell Surface Receptors 85

Dimerization

P P PLC P P PLC

TK TK TK TK TK TK
Pl3K
P P P P GRB2 SOS

P P GAP P P Src
Ras

Figure 3 Schematic of receptor tyrosine kinase (RTK) activation and signaling. Signaling through RTKs is initiated by
binding of ligand, which leads to dimerization of the receptors. Dimerizations result in autophosphorylations of the receptors.
The phosphorylated receptor then serves as a scaffold that organizes a complex signaling machine. A key pathway that is
activated by RTKs is the ras-mediated activation of mitogen-activated protein kinase (MAPK) leading to increased
transcription of immediate early genes.

Table 1 Examples of prominent G-protein coupled receptors

G-Protein type Examples of receptors Major second messenger

Gs -adrenergic receptor Increased cAMP

Endothelin Receptor II
Glucagon
Gi 2-adrenergic Decreased cAMP
5-hydroxytryptamine
(1A)(5-HT(1A))
Acetylcholine
(muscarinic)
Gq Endothelin receptor I Diacylglycerol and IP3
Histamine (H1) receptor Leading to increased intracellular calcium
Angiotensin receptor I
5-HT(1C)
Go Unknown neurotransmitters in brain unknown
Transducin Rhodopsin cGMP
Phosphodiesterase
Decreased cGMP

desensitization occurs when activation of one receptor
pathway causes diminished responsiveness of a number
of receptor pathways that use the same downstream
signaling components. For example, stimulation of the
-adrenergic pathway can result in desensitization of
other receptor systems that utilize cAMP as a second
messenger system (Hoffman and Taylor 2001).
Homologous desensitization occurs when the acti-
vation of the same signaling systems causes
desensitization of the same receptor-activated system.
One of the best-studied examples of homologous
desensitization is agonist-stimulated phosphorylation
~
of the -adrenergic receptor resulting in decreased
sensitivity to further agonist stimulation. -Adrenergic
receptor kinase (BARK) was shown to phosphorylate
the receptor only when the receptor was occupied by
the agonist. Subsequently, other receptor kinase family
members were identified that phosphorylate a wide
86 Receptor Systems
Table 2 Representative integrin heterodimers and their major binding partners
Heterodimer Binding proteins
11 Laminin, collagen
22 Collagen
31 Fibronectin, laminin, collagen
41 Fibronectin, VCAM, osteopontin
51 Fibronectin
61 Laminin, merosin
71 Laminin
v1 Fibronectin, vitronectin
v3 Vitronectin, fibronectin, von Willebrand factor,
fibrinogen, denatured collagen, osteopontin
v5
IIb3 Fibrinogen, fibronectin, von Willebrand factor
array of G-protein coupled receptors. The general
family of kinases is referred to as G-protein receptor
kinases (GRKs). Because these kinases only phosphor-
ylate the agonist-occupied receptors, they provide a
mechanism for achieving homologous agonist-specific
desensitization. For complete desensitization of the
receptor signaling pathway binding of an arrestin
protein is required. The phosphorylated residues on
the cytoplasmic tail of the receptor form the binding
site for arrestin, which in turn serves to attenuate
signaling. The arrestin-bound receptor may then be
targeted for further processing and internalization,
which can lead to either longer-term downregulation
and/or activation of other signaling pathways (DeWire
et al. 2007). Better understanding of these processes will
be important for understanding the mechanism of
action for drugs and for potential targets of toxicants.
2.06.3.2 Pathologies Associated
with G-Protein Coupled Signaling
Mutations in the receptors, G protein, or other reg-
ulatory proteins can lead to either loss of function or
gain of function of the various pathways. Loss of
function mutations may result in agonist resistance
and hence mimic hormone or agonist deficiency.
Gain of function mutations result in constitutive,
agonist-independent signaling and would mimic an
excess of the hormone or agonist. The phenotype of
the mutations can vary depending on the range of
expression of the receptors and whether the mutation
is somatic or germ line. Additionally, mutations in
these pathways can alter cell proliferation and con-
tribute to sensory defects.
G proteins are key targets for bacterial toxins such
as cholera toxin and pertussis toxins. Both of these
toxins act to stimulate cAMP production, but by
Recognition sequence
DGEA
RGD
RGD, EILDV
RGD
RGD
RGD
RGD
RGD
different mechanisms. Cholera toxin ADP-ribosy-
lates the G subunit rendering it constitutively
active and leads to massive increases in cAMP pro-
duction. In contrast, pertussis toxin acts on Gi to
inhibit the inhibition of adenyl cyclase. This pathway
also results in an increase in cAMP production. A
number of other bacterial toxin targets are related to
signal transduction pathways related to G proteins
(Passador and Iglewski 1994). In conclusion, the
GPCR family of receptors and the associated regu-
latory proteins regulate a number of key pathways.
These proteins serve as key targets for bacterial
toxins, pharmacological targets, and sites of numer-
ous pathologies when mutated.
2.06.4 Enzyme-Linked Receptors
As noted above, the GPCRs do not contain any
enzymatic function themselves; the G proteins
serve to link the receptor to the enzymes or effector
systems that regulate production of the second mes-
senger molecules in response to binding of the
stimulus to the extracellular domain of the receptor.
In contrast, enzyme-linked receptors contain cataly-
tic function within the receptor itself that is regulated
in response to agonist binding to the receptor.
Examples of this type of receptor include the ser-
ine/threonine kinase receptors of which the
transforming growth factor (TGF)- receptor is an
example, the guanylyl cyclase receptors including
the atrial natriuretic peptide receptors, ligand-gate
ion channels such as the acetyl choline receptor, and
the most prominent member of this class of receptors,
the tyrosine kinase receptors. For the purpose of this
chapter, we will focus primarily on the tyrosine
kinase receptors (Alberts et al. 2007).

2.06.4.1 Receptor Tyrosine Kinases
The receptor tyrosine kinases (RTKs) are a large
superfamily of receptors that function as the recep-
tors for a wide array of growth factors, including
epidermal growth factor (EGF), nerve growth factor
(NGF), platelet-derived growth factor (PDGF), vas-
cular endothelial growth factor (VEGF), fibroblast
growth factor (FGF), insulin and the insulin-like
growth factors (IGF), and the ephrins and angiopoie-
tins. Most of the RTKs function to regulate complex
functions such as proliferation or differentiation, and
as such the signal transduction pathways often
terminate in the regulation of transcription and
gene expression (Alberts et al. 2007).
The RTKs are characterized by a single trans-
membrane spanning region. The extracellular
region contains the growth factor or ligand-binding
region and the intracellular portion of the receptor
contains the tyrosine kinase enzymic activity. For
most family members, agonist binding initiates the
signaling pathway by bringing two receptors together
to form a dimer. The formation of the dimers allows
for the tyrosine kinase on one half of the dimer to
phosphorylate tyrosine residues on the other dimer.
This process has been referred to as autophosphor-
ylation or transphosphorylation. The phosphorylated
tyrosine residues act as docking sites for enzymes and
other components of the signaling machinery. The
proteins that bind to the phosphorylated tyrosines
usually contain a consensus amino acid sequence
that has been termed src-homology domain 2
(SH2). Among the proteins that bind to activated
RTKs are tyrosine kinases (e.g., members of the src
family), tyrosine phosphatases, adapter proteins (e.g.,
grb), phospholipase , (PLC), and phosphatidyl
inositol 3-kinase (PI 3-kinases). Thus, the activation
of individual RTKs can serve as initiation of multiple
downstream signaling pathways (Alberts et al. 2007).
The resulting signaling events can regulate both
cytosolic and nuclear events. The activation of PLC
results in the generation of the second messenger
molecules diacylglycerol and inositol tris-phosphate.
These molecules regulate the activity of protein
kinase C and the release of intracellular calcium
stores, respectively. The activation of these path-
ways, like the PLC pathway regulated by the
GPCRs, serves to alter contractile and cytoskeletal
properties of the cells in addition to the regulation of
transcriptional events. Activation of PI 3-kinase is
key to the regulation of the Akt signaling pathway
Cell Surface Receptors 87
but RTKs. Akt is a key regulatory pathway governing
cell survival in addition to other regulatory events.
The key pathway regulating cell proliferation and
growth is the activation of the mitogen-activated
protein kinase (MAPK) pathway. The activation of
this pathway is initiated by the recruitment of the
adaptor protein Grb2 to the phosphorylated tyro-
sines on the cytosolic tail of the receptor. This
adapter protein then recruits the GEF, son-of-seven-
less (SOS), which in turn serves to activate the small
GTPase, ras. Ras functions to activate the raf protein
kinase, which in turn activates the MAPK, cascade.
The activation of MAPK results in translocation to
the nucleus where it phosphorylates key transcrip-
tion factors that regulate the transcription of
immediate early genes that go on to regulate the
expression of proteins that initiate cell growth
(Simon 2000).
As key regulators of cell growth and differentia-
tion, each step in the signaling pathway (i.e., growth
factor, receptor, and signaling), when mutated, can
result in cancer, and thus may serve as key sites for
toxicant-induced injury. For example, v-sis is a virally
encoded oncogene that is homologous to PDGF and
competes with PDGF for the binding to its receptor.
Mutation of downstream regulatory proteins such as
ras results in unregulated cell growth and cancer
(Perona 2006). However, the focus of this particular
chapter will be on the receptors themselves.
Aberrant protein tyrosine kinase activity of the
RTK family is linked to the development and progres-
sion of human cancers. The erbB family of receptors
was first implicated in cancer when the avian erythro-
blastosis tumor virus was found to encode an altered
form of the human EGF receptor also known as erbB1.
Mutations in this pathway are also found in many
breast cancers and specific mutations are used to deter-
mine the overall prognosis of the cancer and also to
determine the appropriate treatment plan (Rowinsky
2003). Defects in insulin receptor signaling are asso-
ciated with increased cell proliferation and altered
signaling processes associated with diabetes. These
are only a few of the numerous mutations in RTK-
associated signaling that have been shown to be pri-
mary defects in the initiation of cancer or that function
tumor promoters (Porter and Vailancourt 1998).
In addition to their role in cancer, RTKs play
critical roles in the regulation of many other physio-
logic processes, and breakdown in the normal
processes leads to other disease processes. The
VEGF receptors play important roles in regulating
88 Receptor Systems
angiogenesis or the growth of new blood vessels
(Breen 2007). This process is important in tumor
growth and in metastasis of cancer cells. Platelet-
derived growth factor and its receptors are important
in development of atherosclerosis and other vascular
disorders (Boucher and Gotthardt 2004). In addition,
the insulin receptor and insulin insensitivity are key
regulators of diabetes and related vascular problems
(Nigro et al. 2006).
Like the GPCRs, there are precise mechanisms
for shutting down signaling through the receptors
and these processes are tightly regulated. A major
deactivation pathway, receptor downregulation,
involves ligand-induced endocytosis of the RTK
and subsequent degradation in lysosomes. A complex
molecular machinery that uses the small protein ubi-
quitin as a key regulator assures proper endocytosis
and degradation of RTKs. Data have been presented
above that overactivation of RTK signaling pathways
is strongly associated with carcinogenesis. Newer
data also suggest that inappropriate receptor down-
regulation can also result in oncogenesis (Bache et al.
2004; Kirisits et al. 2007).
2.06.4.2 Transforming Growth Factor-
Receptors
The TGF- family includes the TGF- 1,2, and 3,
the bone morphogenetic proteins (BMPs), inhibins,
and activins. These growth factors play important
roles in development and tissue morphogenesis, and
in adults play important roles in normal tissue remo-
deling and adaptation. Additionally, these pathways
have been linked to specific pathologies. The TGFs
are important in fibrosis of various tissues including
lung, kidney, and liver are important in the patho-
genesis of asthma and renal failure.
The receptors for these growth factors are quite
complex and are composed of multiple subunits. The
generalized structure of these receptors includes inter-
action between type I and type II receptors. Both types
of receptors are transmembrane proteins and contain a
serine/threonine kinase domain. The type 1 receptor
contains a conserved glycine/serine rich sequence
binding of TGF-, which results in the stable associa-
tion of two receptor subunits of each type and
phosphorylation of gly/ser region on the type I recep-
tor by the type II receptor. This sequence of events
results in activation of the type I receptor with sub-
sequent autophosphorylation and the phosphorylation
of the small mothers against decapentaplegic (SMAD)
proteins. SMADs are considered ligand-induced
transcriptional regulators of TGF- signaling.
SMADs activate transcription through DNA binding
and organization of nucleoprotein complex. Signaling
mediated through these receptors are key to renal and
pulmonary fibrosis, cardiovascular disease, and other
pathologies (Feng and Derynck 2005).
2.06.4.3 Ligand-Gated or Receptor-
Operated Ion Channels
Ligand-gated or receptor-operated ion channels are a
special classification of activity-associated receptors.
In this case, instead of activating an enzyme activity
upon ligand binding, ligand binding regulates the
activity of the ion channel. Thus, the relationship is
similar to the enzyme-linked receptors and will be
discussed in this section. Several examples of ligand-
gated ion channels include receptors for several neu-
rotransmitters nicotinic cholinergic receptor,
-aminobutyric acid A (GABA), and receptors for
glutamate, aspartate, and glycine.
The general organization of these receptors is that
they are composed of multisubunits; each subunit
spans the plasma membrane multiple times.
Association of the subunits forms the pore or channel
and changes in conformation of the subunits upon
ligand binding regulates opening and closing of the
channels. Depending on the specific receptor, ligand
binding may occur only on a subunit that appears
once in the overall structure (e.g., sulfonylurea recep-
tor) or multiple ligand binding subunits may be
present (e.g., the nicotinic acetylcholine receptor).
Ligand-gated channels may also be regulated by
protein phosphorylation of the channel subunits sub-
sequent to signaling through other receptors (Sheng
and Pak 2000).
2.06.5 Adhesion Molecules:
Mediators of CellMatrix and CellCell
Interactions
We will review briefly the various types of adhesion
receptors in this section. We will present a brief
overview of the integrin family of adhesion mole-
cules, the selectins, cadherins, and the Ig cell
adhesion molecules (CAMs). These receptors have
been reviewed in detail previously (Juliano 2002).
These receptor molecules play important roles in a
number of basic processes including cell prolifera-
tion, migration, development, and tissue remodeling
in adults. All of these receptor types involved fairly

large extracellular domains that allow for interaction
with extracellular matrix proteins (ECM), and/or
adhesion molecules of adjacent cells, single trans-
membrane domains, and short cytoplasmic tails that
are involved in organizing the actin cytoskeleton and
recruiting signaling molecules. Early studies of these
molecules focused on their roles in adhesion.
In addition to this role, it is now clear that these
receptors play major roles in cell signaling and reg-
ulation of key cellular events.
2.06.5.1 Integrins
Integrins are specialized cell surface receptors that
interact primarily with ECM proteins such as fibro-
nectin, collagen, and laminin. Some specialized
integrins interact with cell surface receptors on other
cells. Integrins are heterodimers composed of an and
a subunit. Currently 18 distinct subunits and 8
-subunits have been identified in vertebrate organ-
isms. The distinct interaction of specific
combinations forms the specificity of interaction with
ECM proteins. Upon interaction with ligand the
integrins undergo conformational changes that result
in reorganization of the cytoskeleton and organization
of complex protein signaling complexes within the
focal adhesion sites (see Figure 4). The affinity of an
integrin for its ECM ligand is modulated by both
intracellular signaling processes and by ions in the
extracellular milieu (Ginsberg et al. 2005).
Engagement of integrins by their specific ECM
ligand results in direct activation of signaling pro-
cesses. The observation that cell adhesion and
resulting integrin clustering lead to increased tyrosine
phosphorylation was a seminal event in beginning to
understand the regulation of signaling processes by
integrin receptors. One of the first molecules to be
discovered was focal adhesion kinase (FAK), a non-
RTK that is now known to become activated by the
integrinmatrix interactions. FAK can also serve as a
scaffolding protein and upon activation and auto-
phosphorylation can interact with other proteins
including c-Src, PI 3-kinase, paxillin, and talin. In
addition to the complex assembly of tyrosine
kinaserelated signaling players that ultimately lead
to the activation of MAP kinase and hence contribute
to cell cycle regulation, activation of integrin signal-
ing cascades plays an important role in activating
small GTPases such as rho, rac, and cdc 38. These
proteins are critical in regulating the organization of
both actin stress fibers and cortical actin around the
perimeter of the cell. Thus, upon integrin activation a
Cell Surface Receptors 89
ECM
integrin integrin
actinin
Talin
n
uli
nc
Actin
Vi
FAK
Src
Figure 4 Schematic of integrin and relationship to
extracellular matrix and cytoskeleton organization. Integrins
are heterodimers composed of an and subunit. The
external domains form the binding site for interaction with
extracellular matrix proteins (ECMs). The short cytoplasmic
tail interacts with actin-binding proteins and a variety of
signaling molecules including FAK and c-Src. Integrins can
mediate both outsidein signaling and insideout signaling.
number of other signaling and actin-binding proteins
become associated with the complex leading to the
formation of the complex structure of the focal adhe-
sion kinase. These processes have been reviewed in
more detail elsewhere (Romer et al. 2006).
The complex nature of the integrinligand speci-
ficity has been extensively studied because of the
relationship between integrin binding and a number
of crucial cellular events. The identification of the
peptide sequence in fibronectin that interacted with
51 integrin was an important step in understand-
ing the interaction of specific integrins with the
ECM. The sequence Arg-Gly-Asp (RGD) was
found to be the core sequence involved in interacting
with a number of integrin heterodimers with sur-
rounding sequences adding to the specificity.
Peptides have been used to decipher the role of
specific integrins in cellular responses. It has been
harder to identify the exact amino acid that bind
integrins. Sequence in more complex ECM proteins
such as laminin have been harder to identify the
precise sequences involved in binding to specific
integrins; however, this is a promising area of
research as an arsenal of different peptide mimetics
90 Receptor Systems

could then be used to differentially antagonize spe- 2.06.5.3 Selectins and Ig CAM Adhesion
cific integrins or as scaffoldings for tissue engineering Molecules
(reviewed in Takagi (2007); Temming et al. (2005)).
Compared to the integrins and cadherins, relatively
In addition to modulation of intracellular signal-
little is known about the signaling processes mediated
ing by binding of matrix to the integrin (outsidein
by members of the Ig CAM and selectin cellcell
signaling), integrin with the extracellular matrix can
adhesion molecules. The Ig CAM family members are
be modified by intracellular signaling processes
characterized by large Ig-type repeats in the extracel-
(insideout signaling). It is now clear that focal
lular domain with a single transmembrane domain and
adhesion/integrin signaling processes play very
a short cytoplasmic tail. It is known that members of this
important roles in regulating complex cellular
family are involved in neural development and in
events. In particular, it became clear that regulation
immune cell interaction with endothelial and other
of cyclic progress requires key signals from the
tissue cells. These molecules play key roles in mediat-
integrins. In particular, specific integrins seem to be
ing the immune response and targeting leukocytes to
key for complex signaling through specific RTKs
the tissues. In this role, the expression, activation, and
(Ginsberg et al. 2005).
signaling are key to the regulation of inflammatory
Construction of mouse models in which the
responses (Juliano 2002).
expression of specific integrins is null has aided in
The selectins (L-, E-, and P-) also have large extra-
our understanding of the complex relationship
cellular domains that contain lectin-like domains,
between specific integrins in development and their
EGF-like domains, and complement regulatory
contribution to specific disease (Bouvard et al. 2001).
domains with a single transmembrane domain and a
The use of mouse models and individual deletions of
short cytoplasmic tail. The selectins are important in
integrin subunits has allowed for the determination
mediating heterotypic cellcell interactions such as
of the contribution of individual integrins to specific
between immune cells and platelets with endothelial
processes. For example, deletion of the 1 subunit
cells during inflammatory events and wound healing.
results in embryonic lethality because of its extensive
Much less is known about the signaling pathways that
involvement in many processes and its interaction
are activated by these interactions, but it is likely that
with numerous subunits (Fassler and Meyer 1995;
the short cytoplasmic tail also serves to recruit signaling
Werner et al. 2000). Other deletions result in more
molecules and to interact with the actin cytoskeleton so
localized defects, such as the deletion of the 7
that binding can initiate complex cellular behavior.
subunit leads primarily to a muscular dystrophy
phenotype ref.

2.06.5.2 Cadherins 2.06.6 Conclusions

The cadherins are calcium-dependent homotypic
cellcell receptors. The classic cadherin family mem-
bers include N, P, R, B, and E cadherins, each of
which contains 100 common amino acid repeats in
their large extracellular domain. Cadherins localize
to specific regions in the plasma membrane known as
adherens junctions and interact with like cadherins
on adjacent cells. These cellcell interactions are
important in forming cell barriers and polarization
of cells. On the cytosolic tails, the cadherins interact
with proteins termed catenins (,) that link the
cadherins to the actin cytoskeleton. In this regard,
the cadherins are similar to the integrins, in that upon
binding they serve to regulate the organization of the
actin cytoskeleton and to activate signaling cascades
(Juliano 2002). Modulation of cadherin receptors is
known to occur in various diseases including both
toxicant- and aging-induced renal failure.
Cell surface receptors play an essential and pivotal role
in mediating the response of cells to external stimuli.
The varied receptors allow cells to respond to a wide
range of stimuli ranging from ions to large ECM
proteins that lead to activation of specific signaling
processes and changes in cellular behavior. Any muta-
tion that leads to unregulated or inactive signaling can
lead to pathologies. Thus, cell surface receptors are key
to the mechanism of many chemical toxicants and
serve as targets for the development of drugs.
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