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REVIEW
Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97201, USA
The rapid and reversible phosphorylation of proteins catalyzed by protein
kinases and protein phosphatases is a well recognized mechanism of regulation
in cells. This bidirectional process is a highly flexible method of
influencing cellular activity in response to a variety of incoming stimuli. A
physiological role for protein phosphorylation was first identified about 50
years ago while investigating the regulation of glycogen metabolism
(Fischer and Krebs 1955
;
Sutherland 1972). In fact,
many aspects of gene regulation; cell cycle control, transport, and secretion;
actin remodeling; and cell adhesion are controlled by this mechanism
(Krebs 1985;
Hunter 1995;
Pawson and Scott 1997;
Cohen 2000;
Goodman and Smolik 2000;
Pawson and Nash 2000). The
utility of protein phosphorylation as the predominant form of covalent
modification of proteins in vivo is exemplified by the finding that 
30%
of intracellular proteins are phosphoproteins
(Hunter 1987). Not
surprisingly, the breakdown in signal transduction may be the cause or
consequence of many diseases, including cancer, diabetes, arthritis, and
Alzheimer's (Cohen 1999).
Most signaling pathways are composed of common elements. The initial signal
is transduced through a receptor at the plasma membrane (such as a G-protein
coupled receptor, or a receptor tyrosine kinase or phosphatase), which results
in activation of the receptor or the mobilization of receptor-associated
proteins to generate some form of intracellular message. This signal is then
directed throughout the cell either by the diffusion of a small soluble second
messenger or the translocation of an activated enzyme. At a molecular level,
phosphorylation mediates the regulation of enzymatic activities by causing
allosteric conformational changes, or by directly enhancing or blocking access
to enzyme catalytic sites (Johnson and
Barford 1990; Barford et al.
1991; Johnson and O'Reilly
1996). More recently it has been realized that an essential
feature of signaling by protein phosphorylation is the modulation of
protein–protein interactions. These are mediated by a growing number of
protein interaction modules including WW, SH2, PTB, 143-3, WD-40, FHA, and FF
domains that may associate with their binding partners in a
phosphorylation-dependent manner (Cantley
et al. 1991; Pawson and Gish
1992; Pawson
1995). These protein–protein interactions generate molecular
networks that drive intracellular signaling events. This fascinating topic was
recently the subject of several excellent reviews
(Burack and Shaw 2000;
Hunter 2000;
Jordan et al. 2000;
Pawson and Nash 2000;
Sudol and Hunter 2000). In
this article we emphasize how the subcellular location of protein kinases and
phosphatases provides a means to restrict where and when phosphorylation
events occur. In particular, we discuss the compartmentalization of the
cAMP-dependent protein kinase (protein kinase A; PKA) through its association
with A-kinase anchoring proteins (AKAPs).
 |
cAMP-dependent signaling mechanisms |
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 Top cAMP-dependent signaling... The AKAP modelConclusions and PerspectivesAcknowledgmentsReferences |
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; Rall and
Sutherland 1958). However, this discovery as well as the
development of the second messenger concept was not fully appreciated until a
cAMP-dependent protein kinase was characterized over a decade later
(Walsh et al. 1968). Ever
since this initial discovery, an intense global research effort has elucidated
many molecular and cellular actions of cAMP. Engagement of transmembrane
receptors and the recruitment of intermediary G proteins activate adenylyl
cyclases on the inner face of the plasma membrane
(Tang and Gilman 1992). This
cascade of events triggers an elevation of cAMP in certain intracellular
compartments (Barsony and Marks
1990; Adams et al.
1991; Bacskai et al.
1993). Although cAMP modulates the activities of molecules such as
cyclic-nucleotide gated ion channels
(Kaupp and Seifert 2002),
guanine nucleotide exchange factors (GEFs;
de Rooij et al. 2000), and
cyclic-nucleotide phosphodiesterases
(Houslay 2001), the
predominant intracellular receptor for this second messenger is the
cAMP-dependent protein kinase (PKA).
Most cell types express multiple cAMP-dependent protein kinase forms. The
PKA holoenzyme is a tetramer composed of two catalytic (C) subunits that are
held in an inactive state by association with a regulatory (R) subunit dimer
(Corbin et al. 1973;
Corbin and Keely 1977;
Potter et al. 1978;
Potter and Taylor 1979). The
catalytic subunits (C) are expressed from three different genes; C
,
C
, and C
, whereas the regulatory subunits (R) are expressed from
four different genes; RI, RI, RII, and RII
(Lee et al. 1983;
Scott et al. 1987;
Chrivia et al. 1988). The R
subunit is a modular protein containing an NH2-terminal
homo-dimerization domain, a pseudosubstrate/autophosphorylation site that
serves as the principal site of contact for the C subunit, and two
cAMP-binding sites. Binding of cAMP to the R subunits relieves the
autoinhibitory contact, causing the C subunits to dissociate and allowing
phosphorylation of substrates (Wang et
al. 1991; Gibbs et al.
1992). Two subtypes of the PKA holoenzyme can be formed. The type
I PKA (composed of RI dimers) is thought to be predominantly cytoplasmic and
is most highly expressed in the immune system, whereas type II PKA (composed
of RII dimers) associates with specific cellular structures and organelles and
is abundant in the heart and brain (Scott
1991).
One remaining question in PKA signaling is how this "broad
spectrum" kinase can be implicated in the specific regulation of so many
physiological processes. This is compounded by evidence that multiple agonists
that engage a ubiquitous cAMP synthesis pathway initiate specific PKA
phosphorylation events (Livesey et al.
1982). Accordingly, the mechanism by which PKA distinguishes
between its substrates is a topic of intense investigation. This is
particularly true in the brain, where PKA substrates such as ligand-gated and
voltage-gated ion channels are clustered together at synapses, yet changes in
the phosphorylation state of either substrate cause distinct changes in
synaptic plasticity (Brandon et al.
1995,
1997;
Malenka and Nicoll 1999;
Kind and Neumann 2001;
Malinow and Malenka 2002;
Sheng and Kim 2002). One
explanation for this phenomenon is that compartment-specific pools of PKA are
activated in close proximity to these channels. However, this can only occur
if there is a means to selectively manipulate subcellular pools of cAMP.
Accordingly, it has been proposed that a balance of adenylyl cyclase and
phosphodiesterase activities leads to establishment of intracellular gradients
of cAMP (Dell'Acqua and Scott
1997). Within these theoretical "nano-compartments",
the activation state of PKA is believed to mirror the ebb and flow of second
messenger levels (Beavo and Brunton
2002; Zaccolo and Pozzan
2002). In order to maintain PKA at these sites,
"organizing" proteins called AKAPs exist to restrict the diffusion
of the kinase and place the enzyme close to certain substrates
(Rubin 1994;
Colledge and Scott 1999;
Skalhegg and Tasken 2000;
Kapiloff 2002;
Smith and Scott 2002). This
review concentrates on the role of AKAPs as molecular mediators of PKA
signaling specificity in the brain.
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The AKAP model |
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TopcAMP-dependent signaling...The AKAP modelConclusions and PerspectivesAcknowledgmentsReferences |
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; Bregman et al.
1989). Neuronal proteins, such as MAP2 and p75 (now known as
AKAP75) were initially designated "RII-binding proteins" on the
basis of their ability to remain tightly associated with the type II R
subunits during affinity purification on cAMP-sepharose
(Theurkauf and Vallee 1982;
Bregman et al. 1989). The
development of a modified Western blot procedure called the RII-overlay led to
the identification of additional AKAPs in the brain and most other tissues
(Lohmann et al. 1984;
Carr and Scott 1992). This
technique was subsequently adapted for use in an interaction cloning strategy
where radiolabeled RII was used as a probe to screen cDNA expression libraries
(Bregman et al. 1991; Carr et
al.
1992a,b;
Coghlan et al. 1994). Using
this and related techniques, upwards of 30 AKAPs have been identified
(Colledge and Scott 1999;
Bauman and Scott 2002). Most
AKAPs share three common properties (Fig.
1): (1) an R subunit-binding sequence, (2) unique localization
signals that target the PKA/AKAP complex to membranes, organelles, and
subcellular environments, and (3) additional enzyme-binding sites that permit
the formation of multiprotein signaling complexes. Each of these properties is
discussed below.
|
Common PKA anchoring domains
Most AKAPs contain a recognizable sequence that forms a binding site for
the R subunits. This motif was first identified in the human thyroid anchoring
protein, AKAP-lbc, where a 24-residue peptide called Ht31was generated that
bound RII with nanomolar affinity (Carr et al.
1991,
1992a). The Ht31 sequence is
predicted to form an amphipathic helix, and structural studies indicate that
this region slots into a binding pocket formed by the N-terminal regions of
each RII protomer (Newlon et al.
1997,
1999,
2001). Cellular delivery of
this peptide has become a standard means to delineate a role for AKAPs in the
coordination of cAMP-responsive events by antagonizing PKA anchoring inside
cells (Rosenmund et al. 1994;
Lester et al. 1997;
Vijayaraghavan et al. 1997;
Feliciello et al. 2001;
Moita et al. 2002;
Tavalin et al. 2002). A
consensus PKA anchoring motif called "AKAP-IS" was recently
derived from a comprehensive analysis of 10 AKAPs' sequences and bioinformatic
design of an optimal RII-binding peptide. This 17-residue peptide binds RII
with subnanomolar affinity and disrupts PKA anchoring inside cells
(Alto et al. 2003). The AKAP-IS
sequence has also been used as a motif to screen genomes for potential
AKAPs.
Although AKAPs were initially thought to interact only with the type II PKA
holoenzyme, there is now ample evidence showing that many anchoring proteins
also target the type I kinase (Burton et
al. 1997; Banky et al.
2000; Herberg et al.
2000). Two-hybrid screening and affinity purification techniques
have identified dual-function anchoring proteins that can interact with RI or
RII and, in a few instances, RI-selective AKAPs have been reported
(Angelo and Rubin 1998;
Kussel-Andermann et al. 2000;
Li et al. 2001). It would
appear that RI anchoring also proceeds through the amphipathic helix, although
there may be specific determinants that contribute to the compartmentalization
of the type I PKA holoenzyme. In fact, substitution of aliphatic side chains
in the hydrophobic face of the Ht31helix increases affinity for RI
(Miki and Eddy 1999). In
contrast, anchoring proteins such as D-AKAP-1/sAKAP84/149 and D-AKAP-2 exhibit
less selectivity for either R subunit and have been designated as
dual-function AKAPs (Huang et al.
1997a,b).
Interestingly, recent evidence suggests that a single nucleotide polymorphism
(SNP) that is identified in the aging human population causes a valine to
isoleucine mutation in the anchoring helix of D-AKAP-2. This mutation
increases RI-binding affinity threefold but has no effect on the RII/D-AKAP-2
interaction (Kammerer et al.
2003). In an accompanying paper, those same authors used peptide
array technologies to generate a high-affinity binding peptide with a 100-fold
preference for RI (Burns-Hamuro et al.
2003). Thus it seems likely that reagents will soon be on hand to
permit the selective uncoupling of the type I and type II PKA holoenzymes
inside cells.
Unique targeting regions
Compartmentalization of PKA–AKAP complexes involves specialized
targeting regions on each anchoring protein that participate in
protein–lipid or protein–protein interactions. An emerging
principle is that protein–lipid interactions target the AKAP/PKA complex
to the correct subcellular environment, while additional protein–protein
interactions precisely orient the kinase toward its substrates. For example,
myristoylation and palmitoylation signals guide the membrane tethering of
AKAP15/18 in close proximity of PKA substrates such as calcium channels and
sodium channels (Fraser et al.
1998; Gray et al.
1998). Yet AKAP15/18 may also be cross-linked to the
1 subunit of the L-type Ca2+ channel via a
modified leucine zipper motif. Mutation of this targeting sequence on
AKAP15/18 prevents kinase anchoring and voltage-dependent potentiation of
Ca2+ channel activity (Hulme et
al. 2002). A parallel mechanism may be in place to precisely
orient AKAP15/18 toward neuronal sodium channels, which are also regulated by
an anchored pool of PKA. Lipid-binding and protein interaction domains act
synergistically to target another anchoring protein, AKAP79/150, to a range of
synaptic substrates (Dell'Acqua et al.
1998). Repeat sequences that bind negatively charged phospholipids
orient AKAP79/150 to the inner face of synaptic plasma membranes, whereas this
anchoring protein is selectively coupled to distinct substrates such as the
AMPA-type glutamate receptor ion channels, calcium channels, or potassium
channels through specific protein–protein interactions
(Colledge et al. 2000;
Dodge and Scott 2000). The
mechanism and functional ramifications of AKAP79/150 targeting are discussed
in detail below.
In some cases, targeting of AKAP complexes to substrates only involves
protein–protein interactions. MAP2 anchors PKA to microtubules through a
C-terminal repeat sequence. Phosphorylation of three PKA sites within each
tubulin-binding repeat destabilizes interaction with microtubules
(Itoh et al. 1997). Genetic
disruption of the MAP2 gene in mice causes a redistribution of the PKA
holoenzyme in neurons that limits certain cAMP-responsive phosphorylation
events and causes a reduction in microtubule density and dendritic length
(Harada et al. 2002). One
substrate is the L-type calcium channel, which was reported to be present in a
macromolecular complex with MAP2, the PKA holoenzyme, and the
2-andrenergic receptor (Davare et
al. 1999). However, cAMP signaling to the L-type calcium channel
is maintained in MAP2 knockout mice by compensatory recruitment of anchoring
proteins such as AKAP79/150 and AKAP15/18 that also functionally couple to the
channel (Gao et al. 1997;
Gray et al. 1997).
There are several instances where multiple AKAPs mediate targeting to the
same organelle. Three anchoring proteins (D-AKAP-1/AKAP149, D-AKAP-2, and
Rab32) anchor PKA at mitochondria (Huang et al.
1997a,
1999;
Alto et al. 2002); two AKAPs
(AKAP350-450/CG-NAP and pericentrin) tether the kinase to centrosomes
(Schmidt et al. 1999;
Diviani et al. 2000), and
Ezrin, WAVE-1, and AKAP-lbc tether PKA to distinct areas of the actin
cytoskeleton (Dransfield et al.
1997a; Westphal et al.
2000; Diviani et al.
2001). Also, an unspecified number of anchoring proteins restrict
kinase localization in sperm (Moss and
Gerton 2001). One explanation for these apparent redundancies may
be the need to always have a pool of anchored PKA at certain sites.
Alternatively, each compartment-specific AKAP may direct the kinase to
different subcompartments where specific substrates reside. This latter
hypothesis implies that the compartmentalization of PKA could be a more subtle
and organized process than was initially appreciated.
Signaling complexes
A most important feature of AKAPs is their ability to interact with several signaling proteins. By simultaneously tethering PKA with enzymes such as protein phosphatases, phosphodiesterases, G proteins, and other protein kinases, these multivalent anchoring proteins coordinate the assembly of signaling complexes that provide focal points for the integration and processing of distinct intracellular signals. The following sections review the role of AKAP signaling complexes in neuronal function.
AKAP79/150
The notion of multivalent anchoring proteins was first proposed for the
AKAP79/150 family, a group of three structurally similar orthologs: human
AKAP79, murine AKAP150, and bovine AKAP75. The first evidence for a
scaffolding function came from a yeast two-hybrid screen using AKAP79 as the
bait that isolated clones for the catalytic subunit of the protein phosphatase
PP2B (calcineurin; Coghlan et al.
1995). This finding explained earlier biochemical evidence that
PP2B copurified with PKA and an unidentified 75-kD protein from bovine brain
extracts (Sarkar et al.
1984). The PP2B-binding site has now been mapped to a region
between residues 315 and 360 of AKAP79, and evidence for the assembly of a
PKA–AKAP79–PP2B ternary complex in living cells was provided by
fluorescence resonance energy transfer (FRET;
Dell'Acqua et al. 2002;
Oliveria et al. 2003). These
experiments demonstrate that PKA and PP2B are precisely targeted to the same
intracellular locus. AKAP79/150 also interacts with the catalytic core of most
protein kinase C (PKC) isoforms via a site within the first 75 residues of the
anchoring protein (Klauck et al.
1996; Faux et al.
1999). This provides a mechanism to direct dormant PKC isoforms to
postsynaptic membranes. Inhibition of the anchored kinase is relieved by
binding of Ca2+/calmodulin in a competitive manner, leading to
liberation of active PKC at the postsynaptic densities
(Faux and Scott 1997). Thus
AKAP79/150 organizes two kinases and a phosphatase that respond to distinct
combinations of second messenger signals at synaptic sites
(Fig. 2). Each enzyme
participates in the control of distinct phosphorylation events. PP2B opposes
the modulation of hippocampal AMPA receptors by anchored PKA
(Tavalin et al. 2002).
AKAP79/150 has also been implicated in anchoring of PKA and PKC close to the
inwardly rectifying potassium channel, Kir2.1
(Dart and Leyland 2001), the
2 adrenergic receptor (Fraser et al.
2000; Cong et al.
2001), metabotropic glutamate receptors (mGluR5) in perirhinal
cortex neurons (Cho et al.
2002), and GABA receptors at inhibitory synapses
(Brandon et al. 2003).
|
Although phospholipid-binding domains tether AKAP79/150 to the synaptic
membranes, more precise orientation of the signaling complex toward particular
substrates is conferred by protein–protein interactions. For example,
AKAP79/150 is recruited to heteromeric NMDA receptor clusters through
interaction with the membrane-associated guanylyl kinase (MAGUK) PSD-95
(Colledge et al. 2000). This
prototypic synaptic adapter protein contains three PDZ domains, one of which
binds to the C-terminal tail of the NMDA receptor, an SH3 domain, and a
guanylyl kinase-like domain which interacts with AKAP79/150. Biochemical
fractionation, co-immunoprecipitation, and immunocytochemical labeling of
cultured hippocampal neurons indicate that AKAP150 and PSD-95 are present at a
majority of excitatory synapses (Colledge
et al. 2000). In contrast, recruitment of AKAP79/150 to AMPA-type
glutamate receptors is mediated via association with another MAGUK protein,
SAP97, which acts as a protein bridge to link anchored PKA with a specific
substrate, the glutamate receptor subtype GluR1
(Colledge et al. 2000). This
elaborate molecular bridging facilitates the phosphorylation of Ser 845 in the
cytoplasmic tail of GluR1, an important regulatory site on the channel that is
modified during chemically induced long-term potentiation (LTP;
Lee et al. 1998).
Dephosphorylation of Ser 845 and attenuation of GluR1channels are mediated by
PP2B. In fact, peptide-mediated disruption of PP2B–AKAP79/150
interaction prevents efficient dephosphorylation of the channel and suggests
that tight coupling of the phosphatase with its substrate is necessary for
modulation of channel activity (Tavalin
et al. 2002).
Orientation of the AKAP79/150 signaling complex toward other synaptic
substrates is achieved by different binding surfaces on the anchoring protein.
The cytoplasmic tail of the KNCQ 2 potassium channel interacts directly with
sites in the central portion of AKAP150. This provides a mechanism to
precisely orient PKC to sites where it can efficiently phosphorylate Ser 534
and Ser 541of the channel. Electrophysiological studies have shown that
activation of PKC in superior cervical ganglion (SCG) neurons results in the
phosphorylation and attenuation of KNCQ 2 channels. The introduction of
protein fragments which disrupt the AKAP150–KNCQ 2 channel interaction
uncouple this effect, suggesting that an intact macromolecular complex of the
channel, anchoring protein, and PKC is required to efficiently attenuate the
potassium channel (Hoshi et al.
2003). As the number of AKAP79/150 binding partners increases it
is clear that a single anchoring protein can only interact with a subset of
these proteins. Thus the postsynaptic environment is likely to contain an
array of AKAP79/150 signaling complexes with unique compliments of proteins
that are engaged in regulation of distinct substrates and molecular
events.
WAVE-1
WAVE-1(also known as Scar-1) is a member of the Wiskott-Aldrich syndrome
protein (WASP) family (Machesky and Insall
1998,
1999;
Machesky et al. 1999;
Rohatgi et al. 1999). It is a
scaffold protein that principally functions to relay signals from the small
GTPase Rac to the Arp2/3 complex, a group of seven related proteins that
function to nucleate actin polymerization and facilitate dendritic branching
of actin filaments (Miki et al.
1998; Robinson et al.
2001). The Dictyostelium discoideum ortholog of WAVE-1was
initially discovered in a genetic screen as a supressor of a cyclic-AMP
receptor involved in chemotaxis (Scar;
Bear et al. 1998).
Subsequently three mammalian orthologs were cloned (WAVE-1, -2, and -3;
Miki et al. 1998;
Suetsugu et al. 1999). These
scaffold proteins act as molecular bridges linking Rho family members to the
Arp2/3 complex. WAVE-1is also a kinase anchoring protein, as it binds PKA and
the SH3 domain of the Abelson tyrosine kinase (Abl;
Westphal et al. 2000).
Proteomic approaches have identified other binding partners that are positive
and negative regulators of WAVE function. Rac promotes WAVE-1activation by
causing the release of an inhibitory complex that includes PIR 121, Nap-125,
and HSPC300 (Eden et al.
2002). In contrast, signaling through Rac is terminated by a
WAVE-1-associated GTPase activating (GAP) protein called WRP
(Fig. 3;
Soderling et al. 2002). Thus
WAVE-1is capable of recruiting different combinations of signaling enzymes at
the neuronal cytoskeleton to control distinct protein phosphorylation and
actin remodeling events.
|
This view is indirectly supported by studies carried out on
WAVE-1"knockout" mice
(Soderling et al. 2003).
Although there are clear morphological changes in the brain architecture of
WAVE-1knockout mice, the most intriguing observations are the range of
behavioral abnormalities detected. Poor performance in the rotarod, inclined
screen, and balance beam tests reflects deficits in sensorimotor function that
are often indicative of a perturbed cerebellar physiology
(Soderling et al. 2003).
Likewise, a loss of WAVE-1from regions of the hippocampus and cortex may
underlie the learning and memory deficits that were exposed in the Morris
water maze. Collectively, these findings define a physiological role for
WAVE-1in the facilitation of behavioral traits that are regulated by a variety
of brain regions. Because the role of WAVE proteins is to provide a molecular
platform to assemble protein networks, it is reasonable to propose that the
removal of a core organizational component such as the scaffolding protein
itself is likely to impede the assembly of these molecular machines. Currently
it is unclear whether spatial perturbation of some or all of the WAVE-1binding
partners contributes to the aberrant behavioral phenotypes observed in the
knockout mice. However, mislocalization of the newly discovered WAVE-1binding
partner WRP may be significant. Happloinsufficiency of WRP has been linked to
3p-syndrome, a severe form of mental retardation in humans with symptoms that
include reduced growth, low IQ, atactic gait, and jerky arm movements
(Endris et al. 2002). These
symptoms are remarkably similar to the impaired cognitive and sensorimotor
functions that were reported for the WAVE-1knockout mice. WAVE-1may thus
facilitate normal neuronal network connectivity by localizing WRP for its role
in the regulation of Rac signaling. Therefore, disruption of actin-based
signaling scaffolds that contribute to the formation of synaptic connections
may interrupt neuronal responses and be a causative factor in certain disease
states. WAVE-1 knockout mice may thus provide an animal model to probe the
molecular mechanisms behind cognitive and sensorimotor impairments. Given the
number of WAVE-1binding partners that have been identified to date, it seems
likely that the combinatorial assembly of individual signaling networks may
provide a mechanism for specifying the assembly and function of filamentous
actin structures. The functional importance of the various proteins that
interact with WAVE-1may be investigated by carrying out "knock-in"
experiments using specific forms of WAVE-1where individual protein-binding
sites are mutated.
AKAP350/CG-NAP/Yotiao A number of AKAP complexes arise from the
alternative splicing of a single gene on chromosome 7q21
(Fig. 4). At least four AKAP
forms are expressed that are targeted to at least three distinct subcellular
locations. Initially, a 120-kD RII-binding fragment was identified and a cDNA
encoding a 350-kD protein was isolated from a KE37 human lymphoblastic cell
library (Dransfield et al.
1997b; Schmidt et al.
1999). These findings correlated with the biochemical
identification of a high-molecular-weight AKAP that was enriched in
centrosomal fractions (Keryer et al.
1993). Around the same time, variants encoding AKAP450 and CG-NAP
were identified by analysis of bacterial artificial chromosomes and yeast
two-hybrid analyses, respectively
(Takahashi et al. 1999;
Witczak et al. 1999). The
latter protein was named CG-NAP on the basis of its detection in centrosomal
and Golgi fractions. Detailed analysis of CG-NAP has identified additional
binding partners that include protein phosphatase 2A, the Rho-dependent
protein kinase PKN, and the protein kinase C epsilon isoform
(Takahashi et al. 1999).
Functional studies propose that enzymes in this signaling complex may
participate in membrane trafficking, microtubule nucleation, and/or in
cell-cycle progression (Takahashi et al.
1999,
2002;
Gillingham and Munro 2000).
Parallel experiments performed on the AKAP450 form suggest that it interacts
with the cAMP phosphodiesterase PDE4D3
(Tasken et al. 2001). This
provides a means to tightly regulate cAMP levels and consequently PKA activity
at the centrosome. Interestingly, the compartmentalized PDE4D3 may also
influence the activation state of the PKA pool that is tethered at this site
through its association with another centrosomal AKAP called pericentrin
(Diviani et al. 2000). Because
AKAP450 and pericentrin both contain a C-terminal pericentrin AKAP450 centrin
(PAC) domain, it is possible that they interact with the same structural
elements at the centrosome (Gillingham and
Munro 2000). This apparent redundancy in PKA anchoring may ensure
that the kinase is always anchored to this organelle for an as yet
unidentified essential role in some aspect of centrosomal function.
|
In contrast, yotiao, the shortest splice variant of this family is targeted
to submembrane sites where it anchors PKA and protein phosphatase 1 (PP1;
Westphal et al. 1999). Yotiao
was identified in a yeast two-hybrid screen for proteins interacting with the
C1exon in the cytoplasmic tail of NR1A subunit of the NMDA receptor
(Lin et al. 1998).
Consequently, yotiao regulates channel activity by altering the
phosphorylation state of hippocampal NR1A receptors. Favoring NR1A
phosphorylation by displacing PP1from yotiao with a PP1-binding peptide or by
inhibiting phosphatase activity with okadaic acid increases NMDA receptor
currents, whereas tonic PP1activity negatively regulates NMDA receptors
(Westphal et al. 1999). This
model of channel regulation mediated by yotiao is depicted in
Figure 5. More recently a
requirement for yotiao targeting of PKA and PP1to GABA(A) receptors at
inhibitory synapses was demonstrated in the dopaminergic regulation of
cognitive processes, and yotiao's interaction with potassium channels was
inferred for the control of certain cardiac functions
(Wang et al. 2002).
Collectively, the AKAP350/450 CG-NAP/yotiao family are capable of targeting
PKA and a plethora of other signaling enzymes (see
Fig. 4) to a variety of
subcellular locations. These complexities are underscored by evidence that
individual enzyme-binding sites and organelle targeting domains are encoded by
different exons. A more detailed analysis will be required to establish
whether each AKAP form transcribed from this gene contains only one targeting
domain. Transcriptional regulation is undoubtedly a critical determinant for
location and composition of each signaling complex maintained by this gene
product.
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Conclusions and Perspectives |
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TopcAMP-dependent signaling...The AKAP modelConclusions and PerspectivesAcknowledgmentsReferences |
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;
Soderling et al. 2002;
Tanji et al. 2002). Another
example is the AKAP79/150-mediated anchoring of PKC for a role in the
suppression of M currents in SCG neurons
(Hoshi et al. 2003).
Undoubtedly, additional cAMP-independent signaling events will be ascribed to
AKAP-mediated targeting of enzymes, and functional signaling complexes may be
formed that do not involve PKA.
One important property of AKAPs is to compartmentalize signal termination
enzymes. This is exemplified by yotiao, AKAP220, and AKAP149, which tether
protein phosphatase 1to oppose the action of anchored kinase counterparts
(Schillace and Scott 1999;
Westphal et al. 1999;
Steen et al. 2000). This
creates an environment where protein phosphorylation is only favored when
kinase activity is sufficiently stimulated to overcome these basal
dephosphorylation events. Another variation on this theme occurs where
anchored signal termination enzymes act upstream of protein phosphorylation
events. For example, AKAP450 and mAKAP colocalize a cAMP-metabolizing enzyme
PDE4D3 with a cAMP-dependent protein kinase such that anchored
phosphodiesterase reduces cAMP levels in the vicinity of the kinase
(Dodge et al. 2001;
Tasken et al. 2001). These
signaling complexes not only contribute to the formation of intracellular
gradients of cAMP but also contribute to the spatial and temporal resolution
of PKA signaling by generating pulses of kinase activity.
In conclusion, it seems appropriate to speculate on some emerging aspects
of AKAP research. These include detailed proteomic dissection of AKAP
complexes (Eden et al. 2002;
Soderling et al. 2002), the
identification of distinct determinants on the AKAPs that confer type I or
type II PKA anchoring (Alto et al.
2003) and the detection of genetic polymorphisms in D-AKAP2 that
may correlate with cardiovascular signaling defects in the aging population
(Kammerer et al. 2003).
Particular mention should be given to behavioral and electrophysiological
studies that have implicated AKAP complexes in the control of neural processes
that underlie different forms of learning and memory. Displacement of PKA from
AKAPs in the lateral amygdala depresses auditory fear conditioning in rats,
whereas treatment of hippocampal slices with anchoring inhibitor peptides
occludes synaptically induced long-term depression (LTD;
Moita et al. 2002; E.M.
Snyder, M. Colledge, R.A. Crozier, J.D. Scott, and M.F. Bear, in prep.).
AKAP79/150 has been implicated in the modulation of both neuronal behaviors,
although more definitive analyses are necessary to confirm this notion. PKA
anchoring may also contribute to the surface expression of AMPA channels by
orchestrating signaling events that promote AMPA receptor endocytosis. On the
basis of their postsynaptic location, AKAP79/150 and yotiao seem reasonable
candidates to fulfill this function, although another possibility is
neurobeachin, a recently identified postsynaptic AKAP that contains a
BEACH-WD40 domain (Wang et al.
2000). This protein is believed to interact with the protein
sorting machinery, including endosomes, lysosomes, and the plasma membrane
(Nagle et al. 1996). Thus
regulation of AMPA receptor trafficking may involve several AKAP networks that
coordinate signaling at different phases of the endocytic pathway. Finally,
exhaustive database searches have traced the conservation of certain AKAPs
from Caenorhabditis elegans and Drosophila melanogaster to
mammals. Perhaps the most intriguing findings come from analysis of the
Zebrafish genome, where WAVE-1, mAKAP, AKAP79, and AKAP18 orthologs have been
identified with surprisingly high homology to their mammalian counterparts.
Characterization and genetic manipulation of these putative AKAPs may provide
a means to study the role of PKA anchoring in neural development.
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Acknowledgments |
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TopcAMP-dependent signaling...The AKAP modelConclusions and PerspectivesAcknowledgmentsReferences |
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Footnotes |
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1 E-MAIL
scott{at}ohsu.edu;
FAX (503) 494-0519. 
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References |
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TopcAMP-dependent signaling...The AKAP modelConclusions and PerspectivesAcknowledgmentsReferences |
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