1 The Howard Hughes Medical Institute, Duke University Medical Center, Durham,
NC 27710, USA
2 Department of Medicine, Duke University Medical Center, Durham, NC 27710,
USA
3 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710,
USA
4 The Geriatrics Research, Education and Clinical Center, Durham Veterans
Affairs Medical Center, Durham, NC 27705, USA
* Author for correspondence (e-mail: lefko001{at}receptor-biol.duke.edu)
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Summary |
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Key words: ß-arrestin, G-protein-coupled receptor, Desensitization, Sequestration, Tyrosine kinase, Mitogen-activated protein kinase
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Introduction |
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To date, four functional members of the arrestin gene family have been
cloned (Freedman and Lefkowitz,
1996; Ferguson,
2001
). Two arrestins, visual arrestin
(Shinohara et al., 1987
;
Yamaki et al., 1987
) and cone
arrestin (Murakami et al.,
1993
; Craft et al.,
1994
), are expressed almost exclusively in the retina, where they
regulate photoreceptor function. The ß-arrestins, ß-arrestin 1
(Lohse et al., 1990
) and
ß-arrestin 2 (Attramandal et al.,
1992
), are ubiquitously expressed proteins whose highest levels of
expression are in the brain and spleen. All members of the family can bind
specifically to light-activated or agonist-occupied heptahelical
G-protein-coupled receptors (GPCRs) that have been phosphorylated by GRKs.
Arrestin binding sterically blocks the receptor-G-protein interaction and thus
plays a critical role in the process of homologous desensitization, the
specific uncoupling of agonist-bound GPCRs from their cognate G proteins.
ß-arrestins, in addition to their role in GPCR desensitization, have additional functions not shared with the visual arrestins. By binding to components of the cellular endocytic machinery, ß-arrestins act as adapter proteins that target GPCRs to clathrin-coated pits for endocytosis. The process of GPCR sequestration is important not only in attenuating GPCR signaling in the continued presence of agonist but also for receptor resensitization and downregulation. In addition, ß-arrestins might have novel functions as GPCR signal transducers. Recent reports suggest that they bind directly to several proteins involved in signal transduction, including Src family kinases and components of the ERK1/2 and JNK3 MAP kinase cascades. By recruiting these proteins directly to the GPCR, ß-arrestins can confer distinct enzymatic activities upon the receptor, which may lead to signals that are important for the regulation of cellular growth or differentiation. Here, we review recent advances in our understanding of the role of ß-arrestins in GPCR signaling, both as terminators of G-protein-dependent signaling processes and as potential transducers of novel signals emanating from GPCRs.
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ß-arrestins as signal terminators |
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ß-arrestins in GPCR desensitization
Desensitization, which begins within seconds of agonist exposure, is
initiated by phosphorylation of the receptor. Second-messenger-dependent
protein kinases, including cyclic-AMP-dependent protein kinase (PKA) and
protein kinase C (PKC), phosphorylate serine and threonine residues within the
cytoplasmic loops and C-terminal tail domains of many GPCRs. Phosphorylation
of these sites is sufficient to impair receptor-G-protein coupling efficiency
in the absence of ß-arrestins. For example, phosphorylation of the
ß2 adrenergic receptor in vitro by PKA is sufficient to impair
receptor-stimulated GTPase activity
(Benovic et al., 1985), and
removal of the PKA phosphorylation sites delays the onset of desensitization
in intact cells (Bouvier et al.,
1988
). Agonist occupancy of the target GPCR is not required for
this process, thus receptors that have not bound agonist, including receptors
for other ligands, can be desensitized by the activation of
second-messenger-dependent protein kinases. This lack of requirement for
receptor occupancy has led to the use of the term heterologous desensitization
to describe the process (Lefkowitz,
1993
).
In contrast, homologous desensitization is mediated by phosphorylation of
the receptor by GRKs and subsequent binding of ß-arrestin
(Fig. 1). There are seven known
GRKs. Rhodopsin kinase (GRK1) and GRK7, a candidate for a cone opsin kinase
(Weiss et al., 1998), are
retinal kinases involved in the regulation of rhodopsin photoreceptors,
whereas GRK2-GRK6 are more widely expressed. Membrane targeting of all of the
GRKs is apparently critical to their function and is conferred by a C-terminal
tail domain (Stoffel et al.,
1997
). GRK1 and GRK7 each possess a C-terminal CAAX motif.
Light-induced translocation of GRK1 from the cytosol to the plasma membrane is
facilitated by the post-translational farnesylation of this site. The
ß-adrenergic receptor kinases (GRK2 and GRK3) have C-terminal
Gß
-subunit-binding and pleckstrin-homology domains, and they
translocate to the membrane as a result of interactions between these domains
and free Gß
subunits and inositol phospholipids. Palmitoylation of
GRK4 and GRK6 on C-terminal cysteine residues leads to constitutive membrane
localization. Targeting of GRK5 to the membrane is thought to involve the
electrostatic interaction of a highly basic 46 residue C-terminal domain with
membrane phospholipids.
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In common with second-messenger-dependent protein kinases, GRKs
phosphorylate GPCRs on serine and threonine residues in their third
intracellular loop and C-terminal domains. GRKs, however, preferentially
phosphorylate receptors that are in the agonist-occupied conformation.
Furthermore, GRK phosphorylation alone has little effect on receptor-G-protein
coupling in the absence of arrestins. Rather, the role of GRK phosphorylation
is to increase the affinity of the receptor for arrestins. In vitro, the
ß-arrestin-1-binding affinity of ß2 adrenergic receptors is
increased 10- to 30-fold following phosphorylation of the receptor by GRK2
(Lohse et al., 1993). It is
the binding of arrestin to receptor domains involved in G protein coupling,
rather than GRK phosphorylation, that leads to homologous desensitization of
the receptor.
The crystal structure of visual arrestin indicates that arrestins contain
two major domains, an N domain (residues 8-180) and a C domain (residues
188-362), each of which is composed of a seven stranded ß sandwich
(Graznin et al., 1998;
Hirsch et al., 1999
)
(Fig. 2). Mutagenesis studies
performed on visual arrestin suggest that the N domain contains regions of the
molecule that are important for recognition of light-activated rhodopsin,
whereas a secondary-receptor-binding region resides within the C domain
(Gurevich et al., 1995
).
Additional regulatory motifs reside at the N- and C-termini of the molecule. A
phosphate sensor region localizes to the linker between the N and C domains
and forms part of the polar core of the protein. Interactions between the
C-terminal tail and the phosphate sensor region that maintain arrestin in an
inactive state are disrupted upon receptor binding, allowing arrestin to bind
with high affinity to the phosphorylated receptor.
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The importance of ß-arrestins in the regulation of GPCR function in
vivo is indicated by data obtained from ß-arrestin-knockout mice.
Homozygous ß-arrestin-1-knockout animals are developmentally normal and
exhibit normal resting cardiac parameters, such as heart rate, blood pressure
and left ventricular ejection fraction. However, the administration of
ß-adrenergic receptor agonists produces an exaggerated hemodynamic
response, which suggests that ß-arrestin 1 plays a role in cardiac
ß-adrenergic receptor desensitization
(Conner et al., 1997).
Homozygous ß-arrestin-2-knockout mice are likewise phenotypically normal,
but exhibit a dramatic potentiation and prolongation of the analgesic effect
of morphine, which is consistent with impaired µ opioid receptor
desensitization in the central nervous system
(Bohn et al., 1999
). In these
animals, the loss of opioid receptor desensitization correlates with an
inability to develop tolerance to the antinociceptive effects of morphine, but
does not prevent the development of opioid dependence
(Bohn et al., 2000
).
ß-arrestins in GPCR sequestration
Internalization of GPCRs, also termed receptor sequestration or
endocytosis, occurs more slowly than desensitization, happening over a period
of several minutes after agonist exposure. It is now clear that GRK-mediated
GPCR phosphorylation and binding of ß-arrestin to the receptor
facilitates the agonist-promoted endocytosis of many GPCRs, including the
ß2 adrenergic, angiotensin II type 1a, m2-m5 muscarinic cholinergic,
endothelin A, D2 dopamine, follitropin, monocyte chemoattractant protein-1,
CCR-5 and CXCR1 receptors (Ferguson,
2001) (Fig. 1). The
extent of ß-arrestin involvement appears to vary significantly depending
on the receptor, agonist and cell type, probably reflecting a variation in
endogeous patterns of GRK and ß-arrestin expression, the specific effects
of agonist and partial agonist drugs on receptor conformation and the
availability of alternative pathways for GPCR endocytosis.
The physical basis for the differential effects of visual arrestins and
ß-arrestins on GPCR endocytosis apparently resides within the C-terminal
tail of the molecule (Fig. 2).
ß-arrestins contain two motifs that allow them to function as adapter
proteins that link the GPCR to components of the clathrin-dependent endocytic
machinery. ß-arrestins, but not visual arrestins, bind with high affinity
and stoichiometry to clathrin in vitro
(Goodman et al., 1996). This
interaction involves binding of an LIEF sequence, which is located between
residues 374 and 377 of ß-arrestin 2
(Krupnick et al., 1997
), to a
region located between amino acids 89 and 100 of the N-terminal domain of the
clathrin heavy chain. In addition, ß-arrestins bind directly to the
ß2 adaptin subunit of the heterotetrameric AP-2 adaptor complex through
an RxR sequence, which is located between residues 394 and 396 of
ß-arrestin 2 (Laporte et al.,
1999
; Laporte et al.,
2000
). The AP-2 complex links many receptors to the clathrin
endocytic machinery by binding to clathrin, dynamin and EPS-15, and is
involved in the initiation of clathrin-coated pit formation
(Kirchhausen, 1999
). Mutation
of the AP-2-binding motif of ß-arrestin 2 does not prevent it from
binding to agonist-occupied ß2 adrenergic receptors but does block the
targeting of receptorß-arrestin complexes to clathrin-coated pits
(Laporte et al., 2000
).
Expression of a dominant inhibitory mutant of dynamin, a large GTPase
necessary for the fission of clathrin-coated pits from the plasma membrane,
impairs the endocytosis of ß2 adrenergic receptors
(Zhang et al., 1996
), which
supports the hypothesis that clathrin-coated pits mediate the endocytosis of
many GPCRs.
The N-ethylmaleimide-sensitive fusion protein (NSF) also binds to
ß-arrestin 1 in vitro and in vivo
(McDonald et al., 1999). NSF
is an ATPase involved in intracellular transport. Overexpression of NSF
enhances ß2 adrenergic receptor endocytosis in HEK-293 cells, which
suggests that the interaction between ß-arrestin and NSF is important for
receptor endocytosis. ß-arrestin activity is further influenced by
binding of phosphoinositides, in particular InsP6
(Gaidarov et al., 1999
). The
phosphoinositide-binding region of ß-arrestin 2 resides within residues
233-251. Mutation of basic residues within this region produces a
ß-arrestin that translocates to the membrane but fails to target ß2
adrenergic receptors to clathrin-coated pits, thereby inhibiting endocytosis
of the receptor.
The endocytic function of ß-arrestin 1 is also apparently regulated by
phosphorylation. Cytoplasmic ß-arrestin 1 is almost stoichiometrically
phosphorylated on S412 (Lin et al.,
1997). Upon translocation to the membrane, ß-arrestin 1 is
rapidly dephosphorylated. An S412D mutant of ß-arrestin 1 that mimics the
phosphorylated state binds agonist-occupied ß2 adrenergic receptors and
mediates desensitization, but binds poorly to clathrin, thereby inhibiting
receptor sequestration. Dephosphorylation of S412, which lies within the
C-terminal regulatory domain, must therefore be necessary for the
receptorß-arrestin complex to engage the endocytic machinery.
Interestingly, the kinases responsible for phosphorylation of ß-arrestin
1 appear to be ERK1 and ERK2 (Lin et al.,
1999
). Since ß-arrestins can form macromolecular complexes
with activated ERKs (DeFea et al.,
2000a
; DeFea et al.,
2000b
; Luttrell et al.,
2001
), leading to localization of the kinases to specific
intracellular compartments, phosphorylation of S412 may represent a mechanism
of feedback regulation of ERK function.
While ß-arrestin 2 is not phosphorylated at its C-terminus, its
endocytic function is regulated by post-translational modification after
binding to the receptor. Both ß-arrestin 2 and ß2 adrenergic
receptors have recently been shown to undergo rapid, ß-arrestin-dependent
ubiquitination in response to agonist binding
(Shenoy et al., 2001).
Ubiquitination of ß-arrestin 2 is catalyzed by the E3 ubiquitin ligase
Mdm2, which binds directly to the ß-arrestin. Ubiquitination of the
receptor is carried out by an as yet unidentified ubiquitin ligase.
ß-arrestin ubiquitination is apparently required for receptor
internalization, whereas ubiquitination of the receptor is involved in
degradation of the receptor but not its internalization.
Work with purified proteins in vitro and in overexpression systems has
revealed little in terms of functional differences between the two
ß-arrestins. However, recent studies of fibroblast lines derived from
mouse embryos (MEFs) lacking either or both ß-arrestins confirm the
hypothesis that ß-arrestin 1 and ß-arrestin 2 exhibit functional
specialization (Kohout et al.,
2001). Desensitization of both ß2 adrenergic and angiotensin
AT1a receptors is impaired in both ß-arrestin 1 and ß-arrestin 2
knockout MEFs and further reduced in the double-knockout cells, which suggests
that the two isoforms are equally effective at inducing desensitization. In
contrast, ß2 adrenergic receptor sequestration is markedly reduced only
in ß-arrestin-2-knockout and double-knockout MEFs, not in ß-arrestin
1 knockouts. Reconstitution of ß-arrestin expression in double-knockout
MEFs revealed that ß-arrestin 2 is 100-fold more potent than
ß-arrestin 1 in supporting ß2 adrenergic receptor endocytosis. AT1a
receptor sequestration is minimally affected in ß-arrestin 1 knockouts
and markedly impaired only in the double-knockout MEFs. This suggests that
either ß-arrestin alone is sufficient for AT1a receptor
sequestration.
ß-arrestins in GPCR downregulation and resensitization
Downregulation of GPCRs, the persistent loss of cell surface receptors that
occurs over a period of hours to days, is the least understood of the
processes controlling GPCR responsiveness. Control of cell surface receptor
density occurs at least partially at the transcriptional level, but the
removal of agonist-occupied receptors from the cell surface and their sorting
for either degradation or recycling to the membrane is also important, at
least in the early stages of downregulation
(Fig. 1). Consistent with this
hypothesis is the finding that downregulation of ß2 adrenergic receptors
does not occur in ß-arrestin-1/ß-arrestin-2 double-knockout MEFs
(Kohout et al., 2001).
Resensitization of a GPCR requires its dephosphorylation and dissociation
from its ligand. Several lines of evidence support the hypothesis that
receptor internalization is required for resensitization of many GPCRs
(Sibley et al., 1986;
Ferguson, 2001
). Preventing
GPCR endocytosis either by pharmocological means, such as treatment with
concanavalin A or hypertonic sucrose, or by using mutant receptors that can
signal and become desensitized, but exhibit defective endocytosis has
demonstrated that sequestration is required for resensitization. In COS-7
cells, overexpression of ß-arrestins enhances the rate of ß2
adrenergic receptor resensitization, which indicates that
ß-arrestin-dependent endocytosis plays a role in the process
(Zhang et al., 1997
).
Shortly after stimulation, phosphorylated ß2 adrenergic receptors
appear in an endosomal vesicle fraction that is enriched in GPCR-specific
protein phosphatase PP2A activity (Pitcher
et al., 1995). Dephosphorylation of the receptor occurs in an
acidified vesicle compartment, as treatment of cells with ammonium chloride,
which neutralizes the acidity of endosomal vesicles, blocks association of the
receptor with the phosphatase and prevents receptor dephosphorylation
(Krueger et al., 1997
).
Our understanding of the role of ß-arrestins in determining the
ultimate fate of internalized GPCRs has been advanced by the use of GFP-tagged
ß-arrestin chimeras that permit visualization of ß-arrestin and
receptor trafficking in live cells (Barak
et al., 1997). Using this approach, Oakley et al. have recently
shown that GPCRs exhibit different patterns of agonist-induced ß-arrestin
interaction, which allow the receptors to be grouped into two distinct classes
(Oakley et al., 2000
)
(Fig. 1). Class A receptors
include the ß2 and
1B adrenergic, µ opioid, endothelin A and
dopamine D1A receptors. These receptors bind to ß-arrestin 2 with higher
affinity than ß-arrestin 1 and do not bind to visual arrestin. In
addition, their interaction with ß-arrestin is transient. ß-arrestin
is recruited to the receptor at the plasma membrane and translocates with it
to clathrin-coated pits; however, the receptorß-arrestin complex
dissociates upon internalization of the receptor, such that, as the receptor
proceeds into an endosomal pool, the ß-arrestin recycles to the plasma
membrane (Zhang et al., 1999
).
Class B receptors, represented by the angiotensin AT1a, neurotensin 1,
vasopressin 2, thyrotropin-releasing hormone and neurokinin NK-1 receptors,
bind to ß-arrestin 1 and ß-arrestin 2 with equal affinity and also
interact with visual arrestin. These receptors form stable complexes with
ß-arrestin, such that the receptorß-arrestin complex
internalizes as a unit that is targeted to endosomes. The structural features
of the receptor that dictate the stability of the
receptorß-arrestin complex reside within specific clusters of
serine and threonine residues in the C-terminal tail of the receptor
(Oakley et al., 2001
). The
C-terminus of ß-arrestin also determines the stability of the
interaction, since a ß-arrestin mutant truncated at residue 383 binds to
the ß2 adrenergic receptor (a class A GPCR) with high affinity and
traffics with it into endosomes.
The stability of the receptorß-arrestin interaction might
dictate the fate of the internalized receptor. The ß2 adrenergic receptor
is rapidly dephosphorylated and recycled to the plasma membrane, whereas the
vasopressin V2 receptor, a class B receptor, recycles slowly. Switching the
C-terminal tails of these two receptors, which converts the ß2 adrenergic
receptor into class B receptor and the V2 receptor into class A receptor,
completely reverses the pattern of dephosphorylation and recycling
(Oakley et al., 1999). Thus,
the formation of a transient receptorß-arrestin complex favors
rapid dephosphoryation and return to the plasma membrane, whereas the
formation of a stable receptorß-arrestin complex retards
resensitization and may favor targeting of the receptor for degradation. This
role of ß-arrestin may have important consequences. A naturally occurring
loss-of-function mutation of the V2 receptor, R137H, which is associated with
familial nephrogenic diabetes insipidus, is constitutively phosphorylated and
localizes to ß-arrestin-associated endosomal vesicles in the absence of
agonist. Mutating the R137H receptor to eliminate high-affinity
ß-arrestin binding re-establishes plasma membrane localization of the
receptor and allows it respond to agonist
(Barak et al., 2001
).
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ß-arrestins as signal transducers |
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ß-arrestin-dependent recruitment of Src family kinases to
GPCRs
The initial evidence suggesting that ß-arrestins function as
tranducers of GPCR signals came from the observation that ß-arrestins can
bind directly to Src family kinases and recruit them to an agonist-occupied
GPCR. In HEK-293 cells, stimulation of ß2 adrenergic receptors triggers
the colocalization of the receptor with both endogenous ß-arrestins and
Src kinases in clathrin-coated pits
(Luttrell et al., 1999). This
colocalization reflects the assembly of a protein complex containing activated
Src, ß-arrestin and the receptor (Fig.
3). Similar results have been obtained in KNRK cells, in which
ß-arrestins are involved in recruiting Src to the neurokinin-1 receptor
(DeFea et al., 2000b
), and in
neutrophils, in which ß-arrestins recruit the Src family kinases Hck and
Fgr to the CXCR-1 receptor (Barlic et al.,
2000
).
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The binding of Src to ß-arrestin 1 is mediated in part by an
interaction between the Src homology (SH) 3 domain of the kinase and
proline-rich PXXP motifs located at residues 88-91 and 121-124 in the
ß-arrestin 1 N domain. A second major site of interaction involves the
N-terminal portion of the catalytic (SH1) domain of Src and additional
epitopes located within the N-terminal 185 residues of ß-arrestin 1
(Miller et al., 2000). Binding
to Src evidently does not preclude ß-arrestin binding to the receptor, as
all three proteins can be isolated as a complex following activation of
ß2 adrenergic or neurokinin NK1 receptors
(Luttrell et al., 1999
;
DeFea et al., 2000b
).
ß-arrestin-mediated Src recruitment has been implicated in several
GPCR-mediated signaling events, including tyrosine phosphorylation of dynamin
(Miller et al., 2000),
activation of the ERK MAP kinase cascade
(Luttrell et al., 1999
;
DeFea et al., 2000b
) and
stimulation of neutrophil degranulation
(Barlic et al., 2000
)
(Fig. 3). Stimulation of
ß2 adrenergic receptors results in the rapid Src-dependent tyrosine
phosphorylation of dynamin (Ahn et al.,
1999
). Deletion of two Src-phosphorylation sites in dynamin I
creates a dominant inhibitory form of the protein that impairs ß2
receptor endocytosis, which suggests that tyrosine phosphorylation represents
a mechanism for modulating dynamin activity. Expression of a mutant Src
protein that contains only a catalytically inactive SH1 domain but still binds
avidly to ß-arrestin selectively inhibits
ß2-adrenergic-receptor-stimulated tyrosine phosphorylation of dynamin and
receptor internalization (Miller et al.,
2000
). These data suggest that one role of the ß-arrestin-Src
complex is to modulate GPCR endocytosis.
The Ras-dependent activation of the ERK1/2 MAP kinase pathway by many GPCRs
requires Src kinase activity (Luttrell et
al., 1996). In some cases, the interaction between ß-arrestin
and Src appears to be important for GPCR-mediated ERK1/2 activation. In
HEK-293 cells, overexpression of ß-arrestin 1 mutants that exhibit either
impaired Src binding or are unable to target receptors to clathrin-coated pits
blocks ß2 adrenergic receptor-mediated activation of ERK1/2
(Luttrell et al., 1999
). In
KNRK cells, activation of NK1 receptor by substance P leads to assembly of a
scaffolding complex containing the internalized receptor, ß-arrestin, Src
and ERK1/2. Expression of either a dominant-negative ß-arrestin 1 mutant
or a truncated NK1 receptor that fails to bind to ß-arrestin blocks
complex formation and inhibits both substance-P-stimulated endocytosis of the
receptor and activation of ERK1/2 (DeFea et al., 2000).
In granulocytes, activation of the chemokine receptor CXCR1 by IL-8
stimulates the rapid formation of complexes containing endogenous
ß-arrestin and Hck or Fgr (Barlic et
al., 2000). The formation of ß-arrestinHck complexes
leads to Hck activation and trafficking of the complexes to granule-rich
regions. Granulocytes expressing a dominant-negative ß-arrestin mutant
that exhibits impaired Src binding fail to activate tyrosine kinases. In these
cells, chemoattractant-stimulated granule release after IL-8 stimulation is
inhibited, which suggests that ß-arrestinHck complexes play a key
role in the trafficking of exocytic vesicles.
ß-arrestins as MAP kinase scaffolds
The MAP kinases are a family of evolutionarily conserved serine/threonine
kinases that are involved in the transduction of externally derived signals
regulating cell growth, division, differentiation and apoptosis. Mammalian
cells contain at least three major classes of MAP kinase: ERKs, JNKs (also
known as Stress-activated protein kinase, SAPK) and p38/HOG1 MAP kinases. The
ERK pathway is important for control of the G0-G1 cell cycle transition and
the passage of cells through mitosis or meiosis. In contrast, the JNK/SAPK and
p38/HOG1 MAP kinases are involved in regulation of growth arrest, apoptosis
and activation of immune and reticuloendothelial cells in response to a
variety of environmental and hormonal stresses
(Kryiakis and Avruch, 1996;
Pearson et al., 2001
).
MAP kinase activity in cells is regulated by a series of parallel kinase
cascades comprising three kinases that successively phosphorylate and activate
the downstream component. In the ERK1/2 cascade, for example, the proximal
kinases, Raf-1 and B-Raf (MAP kinase kinase kinases), phosphorylate and
activate MEK1 and MEK2 (MAP kinase kinases). MEK1 and MEK2 are dual function
threonine/tyrosine kinases that, in turn, carry out the phosphorylation and
activation of ERK1/2. Although all of the intermediates are not fully
characterized, the regulation of the JNK/SAPK and p38/HOG1 MAP kinase modules
also involves a MAP kinase kinase kinase, MAP kinase kinase and MAP kinase
phosphorylation cascade. Once activated, MAP kinases phosphorylate a variety
of membrane, cytoplasmic, nuclear and cytoskeletal substrates. Upon
activation, these kinases translocate to the nucleus, where they phosphorylate
and activate nuclear transcription factors involved in DNA synthesis and cell
division (Pearson et al.,
2001).
In many cases, activation of MAP kinase cascades is controlled by binding
of the component kinases to a scaffolding protein
(Burack and Shaw, 2000;
Pearson et al., 2001
). These
scaffolds serve at least three functions in cells: to increase the efficiency
of signaling between successive kinases in the phosphorylation cascade; to
ensure signaling fidelity by dampening cross talk between parallel MAP kinase
cascades; and to target MAP kinases to specific subcellular locations. The
prototypic MAP kinase scaffold is the Saccharomyces cervisiae protein Ste5p
(Elion, 2001
). In the yeast
pheromone mating pathway, Ste5p binds to Ste11p (a MAP kinase kinase kinase),
Ste7p (a MAP kinase kinase) and to either Fus3p or Kss1p (MAP kinases)
(Choi et al., 1994
). Binding
of yeast mating factor to the pheromone receptor, a GPCR, triggers
heterotrimeric G protein activation. Subsequent translocation of Ste5p to the
plasma membrane in response to the release of Gß
subunits leads to
activation of the Fus3/Kss1 cascade. Although no structural homologues of
Ste5p have thus far been isolated from mammalian cells, several mammalian
proteins that can bind to two or more components of a MAP kinase module, and
might perform analogous scaffolding functions, have been identified. For
example, the JIP family of proteins act as scaffolds for regulation of the
JNK/SAPK pathway (Whitmarsh et al.,
1998
; Yasuda et al.,
1999
).
Recent data suggest that ß-arrestins can function as scaffolds for
some MAP kinase modules (Fig.
4). Stimulation of proteinase-activated receptor 2 (PAR2) receptor
in KNRK cells induces the assembly of multiprotein complexes containing the
internalized receptor, ß-arrestin 1, Raf-1 and activated ERK1/2
(DeFea et al., 2000b). Complex
assembly is apparently required for activation of ERK by the wild-type PAR2
receptor, since it is blocked by expression of a truncated form of
ß-arrestin that inhibits receptor endocytosis. The complexes also appear
to function in the targeting of ERK, as the ß-arrestinERK
complexes are retained in the cytosol. Qualitatively similar results have been
obtained for the angiotensin II type 1a (AT1a) receptor expressed in HEK293
and COS-7 cells (Luttrell et al.,
2001
). AT1a receptor activation results in the formation of
complexes containing AT1aR, ß-arrestin 2 and the component kinases of the
ERK cascade: cRaf-1, MEK1 and ERK2. Upon receptor internalization, activated
ERK2 appears in the same endosomal vesicles that also contain
AT1aR-ß-arrestin complexes. The NK1 neurokinin receptor provides a third
example. Activation of NK1 receptors by substance P causes the formation of
complexes comprising internalized receptor, ß-arrestin, Src and ERK1/2
(DeFea et al., 2000a
). These
data suggest that ß-arrestins function as scaffolds for the ERK1/2 MAP
kinase cascade. If so, they are unique among the mammalian MAP kinase
scaffolds described thus far, in that, in common with Ste5p, their function is
directly under the control of a cell surface receptor.
|
ß-arrestins might also be involved in scaffolding other MAP kinase
pathways. In whole brain lysates and yeast two-hybrid assays, ß-arrestin
2 binds to the neuronal JNK/SAPK isoform, JNK3
(McDonald et al., 2000). When
coexpressed in COS-7 cells, ß-arrestin 2 forms complexes with the MAP
kinase kinase kinase Ask1, the MAP kinase kinase MKK4 and JNK3 but not JNK1 or
JNK2. Ask1 binds to the ß-arrestin 2 N-terminus, whereas JNK3 binding is
conferred by an RRSLHL motif in the C-terminal half of ß-arrestin 2
(MacDonald et al., 2001; Miller et al.,
2001
). This motif, which is not present in ß-arrestin 1,
corresponds to a consensus MAP kinase binding motif that has been identified
in several other MAP-kinase-binding proteins. Overexpression of
ß-arrestin 2 dramatically increases Ask1-dependent phosphorylation of
JNK3. Moreover, ß-arrestin 2 expression causes cytosolic retention of
JNK3 and, following stimulation of AT1a receptors, both ß-arrestin 2 and
JNK3 colocalize to intracellular vesicles. Thus, ß-arrestin 2 can also
behave as a scaffold for the JNK3 MAP kinase cascade, bringing the activity
and spatial distribution of this MAPK module under the control of a GPCR.
The ability of ß-arrestins to control both the activity and spatial
distribution of MAP kinases might have important functional implications. Many
GPCRs simultaneously employ multiple distinct mechanisms to activate MAP
kinases (Gutkind, 1998;
Pierce et al., 2001
). The
angiotensin AT1aR receptor, for example, can activate ERK1/2 not only via
ß-arrestin-dependent pathways but also through G-protein-dependent
signals and crosstalk with classical receptor tyrosine kinases
(Eguchi et al., 1998
;
Heeneman, 2000; Gschwind, 2001). The crosstalk between GPCRs and EGF receptors
accounts for the proliferative response to GPCR stimulation in a number of
systems (Murasawa et al.,
1998
; Castagliuolo et al.,
2000
). In contrast, ß-arrestin-dependent ERK activation does
not lead to proliferative signaling. Wild-type PAR2 receptors, which mediate
ß-arrestin-dependent activation of a predominantly cytosolic pool of
ERK1/2 in KNRK cells, do not stimulate 3H-thymidine incorporation or cell
replication (DeFea et al.,
2000b
).
ß-arrestinERK complexes appear to be relatively stable entities
in that they can be isolated by both gel filtration and by immunoprecipitation
(DeFea et al., 2000a;
DeFea et al., 2000b
;
Luttrell et al., 2001
). Since
ß-arrestins are cytosolic proteins, the formation of stable complexes
between ß-arrestin and activated ERK probably leads to cytosolic
retention of ERK1/2. Significantly, a mutant PAR2 receptor lacking GRK
phosphorylation sites, which cannot bind to ß-arrestin, can still
activate ERK1/2 but does so through a mechanistically distinct
Ca2+- and Ras-dependent pathway. This receptor mutant, unlike the
wild-type receptor, induces nuclear translocation of ERK and stimulates cell
proliferation (DeFea et al.,
2000b
). Thus, the nature of the GPCRß-arrestin
interaction appears to dictate both the predominant mechanism of ERK
activation and, thereby, the consequences of ERK activation.
Little is currently known about the functional role of
ß-arrestinERK complexes. In addition to directly phosphorylating
nuclear transcription factors, ERK1/2 phosphorylates numerous plasma membrane,
cytoplasmic and cytoskeletal substrates
(Pearson et al., 2001). These
include several proteins involved in heptahelical receptor signaling, such as
ß-arrestin 1 (Lin et al.,
1999
), GRK2 (Pitcher et al.,
1999
; Elorza et al.,
2000
) and GAIP (Ogier-Denis et
al., 2000
). One potential role of ß-arrestinERK
complex formation could be to specifically target ERK1/2 to non-nuclear
substrates involved in the regulation of GPCR signaling or intracellular
trafficking. Alternatively, ß-arrestin-bound ERK1/2 might phosphorylate
other cytosolic proteins involved in transcriptional regulation, such as
p90RSK, which in turn relay signals to the nucleus. In such a model,
transcriptional events mediated directly by the nuclear pool of ERK1/2 would
be attenuated, whereas alternative pathways of ERK-dependent transcription
would persist, resulting in an altered pattern of transcription following
activation of the GPCR.
Arrestins in growth, development and disease
Mice lacking the genes for either ß-arrestin 1 or ß-arrestin 2,
despite demonstrated perturbations of GPCR desensitization, exhibit normal
embryological development (Conner et al.,
1997; Bohn et al.,
1999
). Whether this indicates that ß-arrestins are not
required for normal development or that the presence of one ß-arrestin
isoform is sufficient to compensate for the lack of the other is unclear.
However, a homozygous knockout of both murine ß-arrestins results in
early embryonic lethality, a finding that suggests a requirement for arrestins
in development. Better evidence comes from the knockout of the Drosophila
kurtz gene, which encodes a novel nonvisual arrestin
(Roman et al., 2000
). Kurtz is
expressed ubiquitously during early embryonic development and later localizes
primarily to the central nervous system and fat bodies. Mutations in
kurtz that severely reduce its function produce a broad lethal phase
extending from late embryogenesis to the third larval instar that is
characterized by the formation of melanotic tumors within the fat bodies.
Expression of the kurtz gene within the CNS rescues the lethality.
While it remains unclear whether the kurtz mutant phenotype reflects
a requirement for arrestins for the termination of G-protein-mediated signals
or for the transduction of arrestin-dependent signals, the data clearly
support a critical role for arrestins in developmental regulation.
Alterations in visual arrestin function are associated with retinal disease
in flies, mice and humans. Certain forms of hereditary stationary night
blindness, such as Oguchi disease, are attributable to mutations in rhodopsin
kinase or visual arrestin, that result in impaired photoreceptor
desensitization (Nakazawa et al.,
1998; Yamada et al.,
1999
; Dryja,
2000
). Many of these patients progress to the development of
retinitis pigmentosa with the death of photoreceptor cells. Arrestin knockout
mice maintained in continuous or cyclic light, but not in continuous darkness,
experience photoreceptor loss at a rate proportional to the amount of light
exposure, consistent with the hypothesis that constitutive signal flow in the
absence of arrestin leads to photoreceptor degeneration
(Chen et al., 1999
). A
different mechanism, possibly involving arrestin-dependent signaling, has been
demonstrated in several different retinal degeneration mutants in
Drosophila (Alloway et al.,
2000
). In these models, the formation of stable
arrestinrhodopsin complexes leads to apoptotic death of photoreceptor
cells, and deletion of either rhodopsin or arrestin rescues the degeneration
phenotype. The retinal degeneration requires the endocytic machinery,
suggesting that the endocytosis of rhodopsin-arrestin complexes might be a
molecular mechanism for triggering the apoptotic pathway. In light of the data
indicating that ß-arrestin 2 can serve as a scaffold for the JNK3 pathway
(McDonald et al., 2000
), these
results suggest that arrestin scaffolds may be involved in this form of
retinal degeneration.
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Conclusions and perspectives |
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Acknowledgments |
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References |
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