G Protein regulation of MAPK networks
ZG Goldsmith and DN Dhanasekaran
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA
G proteins provide signal-coupling mechanisms to hepta-
helical cell surface receptors and are critically involved
in the regulation of different mitogen-activated protein
kinase (MAPK) networks. The four classes of G proteins,
defined by the Gs, Gi, Gq and G12 families, regulate
ERK1/2, JNK, p38MAPK, ERK5 and ERK6 modules by
different mechanisms. The a- as well as bc-subunits are
involved in the regulation of these MAPK modules in a
context-specific manner. While the a- and bc-subunits
primarily regulate the MAPK pathways via their respec-
tive effector-mediated signaling pathways, recent studies
have unraveled several novel signaling intermediates
including receptor tyrosine kinases and small GTPases
through which these G-protein subunits positively as well
as negatively regulate specific MAPK modules. Multiple
mechanisms together with specific scaffold proteins that
can link G-protein-coupled receptors or G proteins to
distinct MAPK modules contribute to the context-specific
and spatio-temporal regulation of mitogen-activated
protein signaling networks by G proteins.
Oncogene (2007) 26, 3122–3142. doi:10.1038/sj.onc.1210407
MAPK; oncogene; cancer
signal transduction; G protein;
Heterotrimeric guanine nucleotide-binding proteins,
or G proteins, consisting of a-, b- and g-subunits,
transduce signals from heptahelical cell surface receptors
to intracellular effectors (Simon et al., 1991; Hepler
and Gilman, 1992; Conklin and Bourne, 1993). The
a-subunit is a 37–42kDa protein, which contains
the guanine nucleotide-binding pocket along with the
intrinsic GTPase activity. The 35-kDa b-subunit and the
8–11-kDa g-subunit are tightly associated with each
other and are often referred to as a single entity, the
bg-subunit (Simon et al., 1991; Hepler and Gilman,
1992; Conklin and Bourne, 1993). To date, 17 different
a-subunits, five b-subunits and 12 g-subunits have
been identified. However, the amino acid identity of
the a-subunits has been used as a basis for the
classification of G proteins into Gs, Gi, Gq and G12
families in which the a-subunits that show more than
50% homology are grouped together (Simon et al.,
1991). In G-protein-coupled receptor (GPCR)-mediated
signaling pathways, ligand-activated receptors catalyse
the exchange of the bound GDP to GTP in the a-subunit
following which the GTP-bound a-subunit disassociate
from the receptor as well as the bg-subunit. The GTP-
bound a-subunit and the bg-subunit stimulate distinct
downstream effectors including enzymes, ion channels
and small GTPase, thus regulating multiple signaling
pathways including those involved in the activation of
mitogen-activated protein kinase (MAPK) modules
(Johnson and Dhanasekaran, 1989; Hepler and Gilman,
1992; Dhanasekaran et al., 1995; Dhanasekaran and
Prasad, 1998; Rozengurt, 1998).
MAPK modules regulate many critical signaling
pathways including cell proliferation, differentiation
and apoptosis (Fanger et al., 1997; Minden and Karin,
1997; Dhanasekaran and Premkumar Reddy, 1998;
Gutkind, 1998; Garrington and Johnson, 1999; Davis,
2000; Chang and Karin, 2001). Each of these modules
consists of at least three distinct kinases, namely an
upstream mitogen-activated protein (MAP) kinase
(MAP2K) and a downstream MAP kinase (MAPK).
In a typical signaling pathway, growth factor stimulated
small GTPases such as Ras, CDC42, and Rac activate
(MAP4K), following which the MAP kinase cascades
proceed through the sequential phosphorylation of
constituent MAP3K, MAP2K and MAPK (Minden
and Karin, 1997; Dhanasekaran and Premkumar
Reddy, 1998; Davis, 2000; Chang and Karin, 2001).
Activated MAP kinases translocate from the cytosol to
the nucleus where they regulate the activities of various
transcription factors through phosphorylation (Khokh-
latchev et al., 1998; Brunet et al., 1999). GPCRs,
primarily through their cognate G proteins, regulate
thesethree-tier MAPK phospho-relay systems
modulate the expression of specific primary as well as
secondary response genes involved in cell proliferation,
differentiation and apoptosis (Gutkind, 2000; Kranen-
burg and Moolenaar, 2001; Werry et al., 2005). G
proteins have been shown to regulate diverse transcrip-
tion factors such as AP-1 (Araki et al., 1997), NF-kB,
CRE, SRE (Takeuchi and Fukunaga, 2003), ATF1
(Ghosh et al., 2002), STAT3 (Sellers et al., 1999), ELK1
Correspondence: Dr DN Dhanasekaran, Fels Institute for Cancer
Research and Molecular Biology, Temple University School of
Medicine, Philadelphia, PA 19140, USA.
Oncogene (2007) 26, 3122–3142
& 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00
(Todisco et al., 1997), Egr-1 (Gerasimovskaya et al.,
2002), HIF-1a (Sodhi et al., 2000), MEF2 (Fukuhara
et al., 2000a,b) via ERK-, JNK-, p38MAPKs- or ERK5
modules. However, only recently the dynamic and
multilayered mechanisms by which G proteins regulate
these MAPK networks have begun to be unraveled. This
review is focused on analysing the mechanisms by which
G proteins regulate different MAPK networks in a
Regulation of MAPKs by Gs
Gs, defined by the a-subunit Gas, transduces signals
from Gs-coupled heptahelical receptors to adenylyl
cyclase that converts ATP to cAMP and subsequently
to cAMP-mediated activation of protein kinase A
(PKA) (Gilman, 1987; Hepler and Gilman, 1992).
Consequently, as depicted in Figure 1, cAMP as well
as cAMP-activated PKA have been shown to play a
major role in Gas-mediated stimulation as well as inhi-
bition of MAPK modules such as those of ERK1/2,
ERK5 and p38MAPK (Cook and McCormick, 1993;
Graves et al., 1993; Wu et al., 1993; Wan and
Huang, 1998; Zheng et al., 2000; Laroche-Joubert
et al., 2002; Stork and Schmitt, 2002; Dumaz and
Marais, 2005; Houslay, 2006; Pearson et al., 2006).
Gasstimulation of ERK1/2
The initial evidence that Gas is involved in the
regulation of ERK1/2 signaling module consisting
of a MAP3K–MAP2K–MAPK module defined by
Raf, MEK1/2 and ERK1/2, respectively, came from
studies focused on defining the oncogenic pathways
regulated by the gsp oncogene that encodes the
constitutively activated mutants of Gas(Landis et al.,
1989; Lyons et al., 1990). Functional characterization of
these activating mutations indicated that the ectopic
expression of Gascould stimulate ERK1/2 in different
cell types (Faure et al., 1994). Using mutant S49
lymphoma cell lines that lack Gas or PKA, it was
further established that Gasand PKA are required to
couple b2-AR signaling to ERK1/2 module (Wan and
Huang, 1998). Analysis of such Gas-mediated stimula-
tion of ERK1/2 indicated that it was mediated by a
pathway involving Rap-1 and its activation of B-Raf,
one of the isoforms of Raf (Vossler et al., 1997; Wan
and Huang, 1998; Schmitt and Stork, 2000; Weissman
et al., 2002; Dumaz and Marais, 2005; Houslay, 2006;
Wang et al., 2006b). One of the mechanisms through
which Gas activates Rap-1 involves cAMP-mediated
direct activation of EPAC (exchange protein directly
activated by cAMP), a guanine nucleotide exchange
factor (GEF) specific for Rap-1 (de Rooij et al., 1998;
Quilliam et al., 2002; Bos, 2006). In rat kidney cortical
collecting duct cells, it has been shown that the
stimulation of Gasand subsequent generation of cAMP
leads to the activation of EPAC, which stimulates
GDP–GTP exchange in Rap-1. The GTP-bound Rap-1,
thus stimulated, activates B-Raf and the downstream
ERK1/2 modules (Laroche-Joubert et al., 2002). The
observation that the introduction of antibodies to Epac-1,
Rap-1 and B-Raf into these cells inhibited Gs-mediated
activation of ERK1/2 module established the linear
pathway leading from cAMP to the activation of
ERK1/2 module involving Epac-1, Rap-1 and B-Raf
(Laroche-Joubert et al., 2002).
mediated activation of ERKs by phosphorylating C-Raf through PKA. Gashas also been shown to stimulate p38MAPK and inhibit
ERK-5 modules via PKA-dependent mechanism. The dashed lines indicate the pathways that have not been fully resolved.
Gsregulation of ERK1/2. Gasstimulates the B-Raf-mediated activation of ERKs via Rap-1 or Ras and inhibits C-Raf-
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
Although further studies confirmed the role of Rap-1
in Gas-stimulated activation of ERK1/2 module, they
also indicated that Gasstimulation of ERK1/2 module
via Rap-1 involves a Rap-1 GEF other than EPAC in
many cell types (Stork and Schmitt, 2002). The cAMP
30, 50-cyclic monophosphate (8CPT-2Me-cAMP) that
can activate EPAC, but not PKA, proved useful in
identifying the alternate pathway through which Gas
activated ERK1/2 via Rap-1 (Enserink et al., 2002). The
observations that 8CPT-2Me-cAMP stimulated EPAC
but failed to activate Rap-1-dependent activation of
ERK suggested that EPAC might not be involved in
Rap-1-mediated activation of ERK1/2 module in all
the cells (Enserink et al., 2002). Further studies have
indicated that in many cell types, Gas-mediated activa-
tion of ERK1/2 signaling via Rap-1 involves novel Rap-
1-GEF known as Crk SH3 domain-binding guanine
nucleotide-releasing factor, or C3G (Tanaka et al., 1994;
Gotoh et al., 1995). It should be noted here that unlike
the direct activation of EPAC by cAMP (de Rooij et al.,
1998; Quilliam et al., 2002; Bos, 2006), the activation
of C3G requires the PKA-mediated phosphorylation
of Ser-17 of Src (Schmitt and Stork, 2002a; Obara
et al., 2004; Weissman et al., 2002; Wang et al.,
2006b), subsequent Src-mediated activation of Cbl,
Cbl-mediated recruitment of Crk–C3G complex and
Crk-SH3 domain-mediated recruitment as well as
activation of C3G (Ichiba et al., 1999; Schmitt and
Stork, 2000, 2002a). Results from these studies establish
a paradigm in which Gas stimulates ERK1/2 via a
pathway involving cAMP–PKA–Src-mediated activa-
tion of C3G, C3G stimulation of Rap-1 and, finally,
module (Schmitt and Stork, 2000; Weissman et al.,
2002; Obara et al., 2004; Wang et al., 2006b).
Finally, it has also been noted that Gas-cAMP-
mediated activation of Ras is involved in the stimulation
of ERK1/2 modules, as demonstrated in cortical
neurons (Ambrosini et al., 2000), thyrocytes (Tsygankova
et al., 2000), melanocytes (Busca et al., 2000) and
melanoma cell lines (Busca et al., 2000; Amsen et al.,
2006), in addition to COS-7 as well as HEK293 cells
(Norum et al., 2003, 2005). In these cells, Gasstimulates
Ras and the subsequent activation of ERK1/2 modules
via PKA-dependent or -independent mechanism in a cell-
type-specific manner. Thus, Gas-mediated PKA-depen-
dent stimulation of Ras signaling to ERK1/2 module has
been shown to involve a PKA-dependent Ras-GEF
known as Ras-GRF1 in COS-7 and HEK293 cells
(Norum et al., 2005, 2007), whereas PKA-independent
signaling involves a cAMP-responsive but PKA-indepen-
dent Ras-GEF known as CNrasGEF in melanoma cell
lines (Amsen et al., 2006).
Gasinhibition of ERK1/2
Gas-mediated cAMP–PKA signaling pathway has also
been shown to potently inhibit ERK pathways (Cook
and McCormick, 1993; Graves et al., 1993; Wu et al.,
1993). A primary mechanism by which Gasinhibits the
ERK pathway involves PKA-mediated phosphorylation
of a specific isoform of Raf, known as Raf-1 or C-Raf
(Wu et al., 1993; Dhillon et al., 2002). C-Raf contains
three PKA-target Serines, namely Ser 43, 259 and 621
(Morrison et al., 1993), all of which can be phosphory-
lated in vitro by PKA (Wu et al., 1993; Hafner et al.,
1994; Mischak et al., 1996). Mutational analyses of
C-Raf indicated that the Gas-mediated cAMP–PKA
signaling axis inhibits C-Raf through the phosphoryla-
tion of Ser-259 (Dhillon et al., 2002). The PKA
phosphorylation of Ser-259 of C-Raf attenuates the
phosphorylation of Ser-338, which is involved in the
activation of C-Raf (Dhillon et al., 2002), thus providing
a molecular basis for Gas-mediated inhibition of C-Raf–
MEK1/3–ERK1/2 module. In addition, it has been
shown that Gas-cAMP–PKA-mediated activation of
Rap-1 is also involved in the inhibition of C-Raf
containing ERK module in fibroblast cell lines such as
NIH3T3 cells (Schmitt and Stork, 2001, 2002b). This
has been primarily attributed to the close sequence and
structural similarities of the effector domain of Rap-1
with that of Ras, through which Rap-1 binds and
sequesters C-Raf from being activated by Ras (Bos,
1998; Schmitt and Stork, 2001, 2002b).
In summary, it can be surmised that Gasstimulates
B-Raf–MEK–ERK1/2 module via Rap-1 pathway in
cells that express B-Ras. However, Gasstimulates or
inhibits C-Raf–MEK1/2–ERK1/2 modules dependent
on the cell type in which C-Raf is expressed. Whereas
Gas-mediated stimulation of C-Raf–MEK1/2–ERK1/2
activation of Ras, Gas-mediated inhibition involves
PKA-mediated phosphorylation or Rap-1-mediated
sequestration of C-Raf. In light of recent findings that
adenylyl cyclase as well as PKA are functionally and/or
physically compartmentalized through their interactions
with proteins such as ERKs (Gros et al., 2006) or
AKAPs (Dumaz and Marais, 2005; Houslay, 2006), it is
quite possible that the Gas-mediated differential regula-
tion of ERK modules by Gasinvolves different pools of
adenylyl cyclase and/or PKA in a single cell.
Gasregulation of p38MAPK and ERK5
In addition to its role in the regulation of ERK1/2
modules, Gasis involved in the regulation p38MAPK as
well as ERK5 modules through the cAMP–PKA
signaling axis. In cardiomyocytes, it has been demon-
strated that the b2-AR stimulates the activity of p38
MAPK involving the classical Gas-cAMP–PKA me-
chanism (Zheng et al., 2000). Although the mechanism
through which Gascouples to the p38MAPK module is
far from clear, the findings that Rap-1 can stimulate
p38MAPK in diverse cell types (Ahn et al., 2005, 2006)
point to the possible role of Rap-1 in this pathway.
However, such a role for Rap-1 in Gas-mediated
activation of p38MAPK remains to be established.
In the case of ERK5, it has been established that
the cAMP–PKA pathway is involved in inhibition of
the ERK5 module consisting of MEKK2, MEK5 and
ERK5 (Pearson et al., 2006). Interestingly, it has been
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
observed that pretreatment of cells with cAMP inhibited
receptor tyrosine kinase (RTK)-mediated activation
of ERK5 in HeLa, C2C12 and NIH3T3 cells. Analysis
of the underlying mechanism has indicated that
PKA phosphorylates MEKK2 at Ser 153, the phos-
phorylationof which inhibits
upstream activators, presumably
MAP4Ks. Thus, Gas-cAMP–PKA-mediated phosphor-
ylation of MEKK2 potentially leads to the overall
inhibition of signaling by MEKK2–MEK5–ERK5
module (Pearson et al., 2006).
Regulation of MAPKs by Gi
The Gifamily of G proteins is defined by the a-subunits
Gai1, Gai2, Gai3, Gaz, GaoAand GaoB. The identifica-
tion of the activated mutants of Gai2 as the gip2
oncogene in pituitary adenomas as well as tumors of the
ovary and the adrenal cortex (Lyons et al., 1990)
indicated the mitogenic activity of Gai. Studies focused
on defining the molecular basis for such mitogenic
activity identified the role of Gaiin the regulation of the
ERK module (L’Allemain et al., 1991; Pouyssegur and
Seuwen, 1992b). Expression of the GTPase deficient,
constitutively activated mutant of Gai2resulted in the
oncogenic transformation of Rat1 fibroblasts (Pace
et al., 1991; Gupta et al., 1992b). Functional characteri-
zation of the transformed phenotype indicated that
(Gupta et al., 1992a). Subsequent studies have shown
that Gai2 can activate the ERK module through a
diverse set of mechanisms involving either direct or
indirect activation of Ras (Pace et al., 1995; Edamatsu
et al., 1998). In addition to its activation of ERK
modules through these mechanisms, Gaialso appears to
transmit signals to ERK as well as other MAPK
modules via its erstwhile associated bg-subunit (Figure 2;
Crespo et al., 1994; Faure et al., 1994; Koch et al., 1994;
Pace et al., 1995).
Gaistimulation of ERK1/2
Gai-dependent activation of ERK primarily involves the
suppression of two inhibitory pathways. One mechan-
ism involves its inhibitory effect on adenylyl cyclase,
whereas the other involves its inhibitory effect on Rap-1
via Rap-1-GAP protein. The well-characterized signal
transduction role of Gaiis to couple specific receptors to
the inhibition of adenylyl cyclase (Johnson and Dhana-
sekaran, 1989; Tang and Gilman, 1992). Consistent with
this prototypic signaling role of Gai, expression of gip2,
the activated mutant of Gai, resulted in a decrease in the
accumulation of cAMP in cultured cells (Lowndes et al.,
1991; Wong et al., 1991). Such a Gai-mediated decrease
in cAMP levels and subsequent decrease in PKA activity
relieves the inhibitory effect of PKA on C-Raf, thus
potentiating Ras–C-Raf signaling to ERK module
(Radhika and Dhanasekaran, 2001). The observation
that the expression of Gai2 slightly enhances the
activation of C-Raf (Pace et al., 1995) is consistent with
However, Gai has also been shown to activate
the ERK pathway via an alternate Ras-dependent
bg-subunits-dependent mechanisms as depicted. See text for details.
Gi regulation of MAPK network. Gi stimulates the activities of ERK, JNK and p38MAPK through a- as well as
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
mechanism (Pace et al., 1995; Mochizuki et al., 1999).
Using a strategy wherein the expression of a pertussis
toxin-resistant mutant of Gai2in cells treated with PTX
could be used to monitor the effect of A1-adenosine
receptors specifically coupled to the transfected PTX-
resistant Gai2; it was demonstrated that the expression
of Gai2 and subsequent activation by A1 adenosine
receptor led to the stimulation of ERK activity (Pace
et al., 1995). In addition, the coexpression of dominant
negative mutant of Ras inhibited Gai2-mediated activa-
tion of MEK and the downstream ERK, indicating a
role for Ras in this pathway (Pace et al., 1995).
However, an intriguing observation was that there was
no increase in the GTP-bound active form of Ras upon
the stimulation of Gai2 by A1-adenosine receptors.
Thus, although these studies indicated that the activa-
tion of ERK by Gai2 required functional Ras, the
molecular basis for such requirement with little or no
modulation of the activation Ras was not clear.
However, the later observation that Gai2can interact
with Rap-1-GAP provided a molecular basis for a
mechanism in which Gai2can activate ERK through a
Ras-sensitive pathway without directly activating Ras
(Mochizuki et al., 1999). Rap-1 was initially identified as
a Ras-like GTPase that can act as a tumor suppressor
by attenuating Ras-mediated cellular transformation
(Pizon et al., 1988; Kitayama et al., 1989). Rap-1-mediated
suppression of transformation is associated with the
ability of activated Rap-1 to attenuate Ras-dependent
ERK activation by EGF as well as LPA (Cook et al.,
1993). As described earlier, activated Rap-1 through
its Ras-homologous effector domain sequesters C-Raf
(Bos, 1998; Schmitt and Stork, 2001, 2002b), thus
MEK–ERK-signaling module. Gai2
Ras-antagonistic inhibitory activity of Rap-1 by recruit-
ing a specific Rap-1 GTPase activating protein II
(Rap1GAPII), which can downregulate Rap-1 activity
(Mochizuki et al., 1999). Thus, mutational or receptor-
mediated activation of Gai2facilitates the translocation
of Rap1GAPII to the plasma membrane where Rap1-
GAPII accelerates the GTPase activity of Rap-1, there-
byrendering it inactive.
sequestered C-Raf leads to Ras–C-Raf reassociation
and the activation of the downstream ERK1/2 module
(Mochizuki et al., 1999). It is significant to note here
that the pathway deduced from this signaling paradigm
supports a view that Gai2 stimulates Ras-dependent
ERK signaling without directly involving the activation
of Ras by inhibiting the activity of Rap-1.
Gbgistimulation of ERK1/2
Gi has also been shown to stimulate the ERK1/2
signaling module by mechanisms that involve the
disassociated bg-subunits (Crespo et al., 1994; Koch
et al., 1994). Expressing the bg-subunit interacting
COOH domain of the b-adrenergic receptor kinase
(bARK-CT) or Gat, both of which can function as
antagonists of bg signaling by virtue of their ability to
sequester endogenous bg, it has been demonstrated that
the bg-subunit is involved in activation of ERK by a
number of Gi-coupled receptors including m2-muscarci-
nic, a2-adrenergic, D2 dopamine, A1 adenosine and
LPA receptors (Crespo et al., 1994; Koch et al., 1994).
Consistent with these observations, expression of bg-
subunit has been shown to increase the basal activity of
ERK in COS-7 cell (Faure et al., 1994). Further analyses
using a dominant negative mutant of Ras have indicated
that the bg-mediated activation of ERK1/2 module
involves Ras (Crespo et al., 1994; Faure et al., 1994;
Koch et al., 1994). Although bg-subunit-mediated
activation of ERK module has been shown to involve
Ras (Crespo et al., 1994; Koch et al., 1994), the
mechanism through which the bg-subunit couples to
Ras appears to be cell-type specific. However, the
consensus is that the activation of Ras by bg-subunit
involves a tyrosine kinase, the identity of which is
context specific. The immediate step involved in bg-
mediated activation of ERK involves phospholipase-
C-b (PLC) and/or phosphoinositide-3-kinase (PI3K),
both of which can be activated by the bg-subunit
(Camps et al., 1992; Katz et al., 1992; Stephens et al.,
1994; Thomason et al., 1994). Transfection studies using
COS-7 or HEK293 cells have established a model in
which Gi-coupled a2A-adrenergic receptors stimulate
ERK1/2 modules via the released bg-subunits (Lev
et al., 1995; Dikic et al., 1996; Della Rocca et al., 1997).
In this model, bg-subunit released from Gi-heterotrimer
trisphosphate (IP3)-mediated increase in intracellular
Ca2þand Ca2þ–calmodulin-mediated activation of Pyk2
kinase. The Pyk2 kinase thus stimulated, activates Src,
which in turn stimulates Shc adaptor protein leading to
the activation of Ras via the Ras-GEF, mSOS
(Lev et al., 1995; Dikic et al., 1996; Luttrell et al.,
1996; Della Rocca et al., 1997).
In some other cellular contexts, it has been observed,
bg-subunit transmits signals through an Src- and Shc-
independent mechanism involving the phosphorylation
of dynamin II and its association with Grb2 (Kranen-
burg et al., 1997, 1999a,b). In Rat1a and COS-7 cells, it
has been demonstrated that LPA- or thrombin receptor
stimulated release of bg-subunit activates ERK1/2
module via a pathway involving PI3K and PI3K-
mediated activation of a tyrosine kinase that promotes
dynamin II–Grb2 complex formation with the resultant
activation of Ras and the ERK1/2 module (Kranenburg
et al., 1997, 1999a,b). Since dynamin can link Ras-GEF
SOS to Ras (Wunderlich et al., 1999), it is possible that
the dynamin facilitates bg-mediated activation of Ras in
this complex. As dynamin has been shown to play a
critical role in vesicular endocytosis (Hinshaw and
Schmid, 1995; Praefcke and McMahon, 2004), and
vesicular endocytosis has been shown to be required for
H-Ras-mediated activation of ERK1/2 module (Roy
et al., 2002), it is likely that dynamin II-mediated
endocytosis plays a critical role in bg-mediated activa-
tion of ERK1/2. As seen in the case of b-arrestin-
mediated activation of ERK1/2 in endocytic vesicles
(Lefkowitz and Shenoy, 2005), it is possible that
bg-mediated ERK1/2 signaling is not involved in the
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
transmission of signals to the nucleus. However, such a
differential role for bg-dynamin-mediated activation of
ERK1/2 modules remains to be clarified.
Gistimulation of JNK pathway
In addition to the activation of ERKs, Gaias well as the
bg-associated with Gaihas been shown to activate the
JNK module (Coso et al., 1995, 1996; Edamatsu et al.,
1998; Yamauchi et al., 2000). Stimulation of ectopically
expressed m2-muscharinic receptors that couple to Gi-
family of G proteins have been shown to activate JNK
via bg-subunits in COS-7 cells (Coso et al., 1995, 1996).
Similar analysis using mastoparan, which mimics GPCR
activation by directly stimulating G proteins (Higashi-
jima et al., 1990), indicated that JNK could be activated
by both the a- and the bg-subunits of Giin HEK293 cells
(Yamauchi et al., 2000). The use of bg-quenching
bARK-CT established that the mastoparan activation
of JNK involved both Gai and Gbgi in these cells
(Yamauchi et al., 2000). Consistent with this observa-
tion, transient expression of the constitutively activated
mutants of Gai1, Gai2 and Gai3 in HEK293 cells
increased JNK activity. Interestingly, similar constitu-
tively activated mutants of Gaoand Gaz, which belong
to Gifamily, failed to stimulate such JNK activation
(Yamauchi et al., 2000). Thus, the activation of JNK
appears to be restricted to some Giisoforms but not to
other Gi family members such as Gao or Gaz. The
expression of dominant negative Rho and Cdc42, but
not dominant negative Rac, inhibited Gai-mediated
activation of JNK, suggesting a pathway involving Rho
and CDC42 in the activation of JNK by Gai(Yamauchi
et al., 2000). Interestingly, Gai-mediated activation of
JNK was not inhibited by the dominant negative
mutants of MKK4 and MKK7, the upstream MAP2Ks
that are typically involved in the activation of JNKs
(Yamauchi et al., 2000). Thus, although, Rho and
Cdc42 have been shown to stimulate JNK via MKK4 in
HEK293 T cells (Teramoto et al., 1996), Gai-mediated
activation of JNK proceeds through a novel pathway
involving Rho and/or CDCD42 and a hitherto unchar-
acterized tyrosine kinase via an MKK4/7-independent
mechanism (Yamauchi et al., 2000). In contrast, the
pathways involving bg-subunit dissociated from Gai
have been demonstrated to involve Ras and Rac (Coso
et al., 1996). In addition, bg-mediated stimulation of
JNK involves both MKK4 and MKK7, as bg-activated
JNK can be inhibited by the dominant negative mutants
of MKK4 as well as MKK7 (Yamauchi et al., 1999).
Although bg-activation of MKK4 proceeds through
Rho and CDC42, its activation of MKK7 involves Rac
(Yamauchi et al., 1999). Although the physiological
significance is not known, it has been shown that
bg-preferentially activates MKK4 in HEK293 cells.
The signaling network that is being unraveled by these
studies indicates that both Gai and Gbgi activate JNK
(Figure 2). However, in both Gai- and Gbgi-mediated
activation of JNK, a tyrosine kinase is involved in the
activation of the respective small GTPases (Yamauchi
et al., 1999, 2000), presumably involving tyrosine kinase
responsive-specific GEFs (Shou et al., 1995; van Biesen
et al., 1995; Miyamoto et al., 2003). Similar to the
activation of the ERK module by Gbgi-subunit, the
activation of JNK by Gbgiappears to require a PI3K
activity in certain cellular contexts, such as the activa-
tion of Gi-coupled m-opioid receptor (Kam et al., 2004).
Regulation of MAPKs by Gq
The Gq family of G proteins is defined by the
ubiquitously expressed Gaq, Ga11 and hematopoetic
cell-specific Ga14, and Ga15/16subunits (Simon et al.,
1991; Hubbard and Hepler, 2006). All of the family
members have been shown to activate ERK1/2, JNK
and p38MAPK modules. The a-subunits of Gqfamily
of G proteins transduce signals from their cognate
receptors to specific cellular responses via the activation
of the effector PLCb (Johnson and Dhanasekaran,
1989; Simon et al., 1991). Activated PLCb hydrolyses
phosphatidylinositol 4,5-bisphosphate (PIP2) to pro-
duce inositol triphosphate (IP3) and diacylglycerol
(DAG), both of which can activate protein kinase C
(PKC), either directly or indirectly via the release of
internally stored Ca2þ. In addition to these a-subunit-
mediated pathways, the bg-subunit released from Gqcan
also activate PLCb (Camps et al., 1992: Katz et al.,
1992) and transmit signals through both PLC–DAG–
PKC- and PLC–IP3-Ca2þ-mediated signaling pathways
Gqstimulation of ERK1/2
Gaq can stimulate ERK1/2 module via PLC–DAG–
PKC as well as PLC–IP3-Ca2þsignaling mechanisms.
Gaq-activated PKC can stimulate ERK1/2 module by
directly phosphorylating and stimulating C-Raf (Kolch
et al., 1993; Ueda et al., 1996; Schonwasser et al., 1998).
An alternate mechanism involving Ca2þ–calmodulin-
mediated activation of Pyk2 leading to the activation of
Ras and subsequently ERK1/2 module can also be
envisaged (Lev et al., 1995; Dikic et al., 1996; Della
Rocca et al., 1997). However, whether Gaq/11activates
ERK1/2 via the PKC–Raf signaling axis or IP3-Ca2þ–
calmodulin–Pyk2–Src–Ras pathway appears to be cell
type dependent. It has been shown that m1-muscarinic
receptor-mediated activation of Gaq stimulates the
ERK1/2 module via PKC–C-Raf signaling axis in Cos-7
and CHO cells (Hawes et al., 1995). In contrast,
Gq-coupled LPA- or bradykinin receptors activate
ERK1/2 via calcium–calmodulin-dependent pathway
involving Pyk2, Src and Ras (Dikic et al., 1996). In
HEK293 cells, a1-adrenergic receptor-mediated activa-
tion of ERK1/2 appears to involve PKC- as well as
Ca2þ-mediated pathways (Della Rocca et al., 1997).
In addition to these typical Gaq-mediated pathways, it
has also been shown that Gaqcan activate ERK through
a novel mechanism involving a DAG- as well as Ca2þ-
dependent Rap-1-GEF (Guo et al., 2001). Using a
variant of PC12 cells, PC12D, it has been shown that
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
m1-muscarinic receptor stimulation of ERK1/2 modules
is independent of Ras but dependent on Gaq-stimulated
PLCb. More interestingly, it has been shown that
Gq-mediated release of DAG and Ca2þleads to the
activation of a calcium- and diacylglycerol-regulated
guanine nucleotide exchange factor, CalDAG-GEFI
that can stimulate Rap-1, which in turn, can activate
B-Raf and the downstream ERK1/2 module (Guo et al.,
2001). Thus, Gaq-mediated signaling to ERK1/2 module
appears to involve three distinct mechanisms: (1)
PKC-mediated activation of C-Raf; (2) Ca2þ-Pyk2-
Src-dependent activation of Ras; and (3) Ca2þ–
DAG-stimulated Rap1-mediated activation of B-Raf.
As Gaq/11activation results in the generation of both
DAG and IP3, all of these mechanisms need not be
mutually exclusive. It should be noted here that since bg-
subunits disassociated from Gq/11-coupled receptors can
also stimulate PLCb, it is possible that they also
contribute to Gq/11signaling to ERK1/2 modules in a
similar manner. However, it has been noted that
PKC- and/or IP3/Ca2þsignaling pathways, rather than
bg-subunits, to activate ERK1/2 modules (Blaukat
et al., 2000). A footnote here is that in some cellular
contexts, as in the case of the activation of ERK1/2
by Gq-coupled oxytocin receptors, the bg-disassociated
from Gqactivates ERK1/2 through the transactivation
of receptor tyrosine kinase (Zhong et al., 2003).
Gqstimulation of JNK
In contrast to the major role of the a-subunits of the Gq
family in activating the ERK module, the a- as well as
the bg-subunits of Gqplays determinant roles in the
activation of JNK module (Coso et al., 1995, 1996;
Mitchell et al., 1995; Zohn et al., 1995; Nagao et al.,
1998). Receptors that couple to Gq such as the m1-
muscarinic (Coso et al., 1995), m3-muscarinic (Wylie
et al., 1999), angiotensin II (Zohn et al., 1995), a1
adrenergic (Ramirez et al., 1997) thrombin (Shapiro
et al., 1996) and endothelin-1 (Shapiro et al., 1996)
receptors have been shown to potently stimulate the
JNK module. The findings that Gaqactivates MEKK1
and MEKK1 deficiency disrupts Gaq-mediated activa-
tion of JNK suggest that MEKK1 is a primary signaling
hub for the activation of JNK by Gaq(Minamino et al.,
2002). However, the molecular mechanism(s) through
which Gqcommunicates to the JNK module appears to
be cell-type specific. Using ectopic expression of Gq-
coupled m1-muscarinic receptors in NIH3T3 (Coso
et al., 1995), Rat1a (Mitchell et al., 1995), COS-7 (Coso
et al., 1996) or HEK293 cell (Nagao et al., 1998), it has
been shown that the stimulation of these receptors lead
to the potent activation of JNK module. While, Gq-
coupled m1-muscarinic receptor activation of JNK does
not involve the PLC-PKC axis in NIH3T3 cells (Coso
et al., 1995), studies with COS-7 cells indicated that the
activation of JNK by m1-muscarinic receptor involves a
α αq q
Ca2þ-dependent pathways as illustrated (see text for details). In addition, the bg-subunits can initiate similar pathways through their
ability to activate PLCb and/or PI3K. The dashed lines indicate the pathways that need to be further characterized.
Gqregulation of MAPK network. Gaqstimulates ERK, JNK, p38MAPK and ERK5 modules via PKC- as well as
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
pathway initiated by the Gbgq-involving Ras and Rac-1
(Coso et al., 1996). In contrast, studies using Rat1a cells
have shown that m1-muscarinic receptor activation of
JNK by Gaq involves a Ca2þ-dependent mechanism
(Mitchell et al., 1995), thereby suggesting a role for the
Gaq-PLC-IP3 signaling axis. Likewise, it has been
shown that Gaq-coupled angiotensin II receptor activa-
tion of JNK proceeds through such Ca2þ-dependent
signaling, possibly involving a PLC-IP3-based mechan-
ism (Zohn et al., 1995). Interestingly, such Ca2þ-
dependent signaling has also been shown to be sensitive
to genistein, suggesting a role for Ca2þ-dependent
tyrosine kinase phosphorylation (ibid). In addition, a
direct role for PKC in the activation of JNK has also
been established. In HEK293 cells, it has been shown
that the expression of the constitutively activated
mutant of Ga11results in the activation of JNK through
a pathway involving PKC as well as Src family of
tyrosine kinases (Nagao et al., 1998).
The general mechanism emerging from these studies is
that Gq can use both the a- as well as bg-subunits
involving the PLC–DAG–PKC as well as the PLC-IP3-
Ca2þsignaling arms to activate JNK. Src- or an Src-like
kinase appears to be involved in the activation of JNK
in both the pathways (Zohn et al., 1995; Nagao et al.,
1998). Therefore, PKC activation of Src and subsequent
Src-mediated activation of Rac through a specific GEF
appears to be involved in Gaq-mediated activation of
JNK via the pathway involving PKC, Src and Rac
(Servitja et al., 2003). Although such a linear pathway
has not been established in a specific single cellular
context, the previous findings that PKC can readily
activate Src through direct phosphorylation (Gould
et al., 1985; Moyers et al., 1993), Src can activate Rac-
specific GEFs (Servitja et al., 2003) and such activation
of Rac can stimulate the JNK module (Crespo et al.,
1996; Michiels et al., 1997) strongly points to such a
Activation of JNK module by the PLC-IP3-Ca2þarm
of Gaqsignaling has been shown to involve a Ca2þ-
dependent activation of Pyk2 (Tokiwa et al., 1996;
Blaukat et al., 1999), Pyk2-induced activation of Src,
Src-mediated phosphorylation of p130CAS and the
subsequent association of p130CAS and the adaptor
protein CrkII (Blaukat et al., 1999; Kodama et al.,
2003). Interestingly, the p130CAS–CRKII complex has
been shown to stimulate the JNK module via Rac-1
(Dolfi et al., 1998; Girardin and Yaniv, 2001) presum-
ably through the activation of Rac-1 by the Rac-GEF,
DOCK180 (Kiyokawa et al., 1998) or R-Ras by the
R-Ras/Rap-1-GEF, C3G (Mochizuki et al., 2000).
Therefore, the signaling from Gaqvia PLC-IP3-Ca2þ
is likely to involve Rac-1- or R-Ras-dependent mechanisms,
both of which can lead to the activation of JNK module
by stimulating JNK-specific MAP4Ks such as MLK3
(Teramoto et al., 1996; Tanaka and Hanafusa, 1998).
Since bg-subunits can stimulate PLC-b and subse-
quent IP3-mediated Ca2þrelease/influx, it should be
noted here that the bg-signaling, leading to the activa-
tion of JNK via Ras and Rho family of GTPases,
involves a pathway similar to the one described for Gaq.
Gqstimulation of p38MAPK
Similar to its role in the activation of the JNK module,
different Gq-coupled receptors have been shown to
activate the p38MAPK module (Kramer et al., 1995;
Krump et al., 1997; Yamauchi et al., 1997). Further
studies have established that Gqcan activate p38MAPK
module through a- as well as the bg-subunits (Yamauchi
et al., 1997, 2001; Nagao et al., 1998; Huang et al.,
2004). The basic mechanism through which Gaq
activates p38MAPK is not different from the one
involved in the activation of the JNK module. The
PLC–DAG–PKC signaling arm of Gaqalong with the
activation of Src or an Src-like tyrosine kinase has been
shown to be involved in Gaq-mediated activation of
p38MAPK (Nagao et al., 1998; Yamauchi et al., 2001).
Thus, the signaling pathways mediated by Gaqinvolve
PLC-PKC-dependent activation of Src followed by Src
activation of the Rho family of GTPases leading to the
activation of p38MAPK module. Consistent with this
view, it has been shown that Gaqactivates MKK3 or
MKK6, the MAP2Ks of p38MAPK module, via
CDC42, Rac and Rho (Yamauchi et al., 2001). The
observations that the Rac-specific GEFs Tiam-1 and
Ras-GRF, both of which can be activated by Src, are in
physical complex with MKK3 and p38MAPK (Buchs-
baum et al., 2002) provides partial evidence for such a
pathway that can be activated by Gaq.
In contrast to the role of PLC-PKC in Gaq-mediated
pathways, the bg-pathways derived from the Gqhetero-
trimer involves a PLC-independent mechanism(s) invol-
ving Rho family of GTPases and a tyrosine kinase that
remains to be identified (Yamauchi et al., 2001). In
addition, it has been shown that Gq-derived bg-subunit
can activate p38MAPK via a pathways involving Rap-1
(Huang et al., 2004). It is quite likely that the activation
of Rap-1 by bg-subunits involves a Pyk2-Src-C3G
pathway similar to the one involved in the activation
of JNK (Mochizuki et al., 2000). Although the mechan-
ism by which Rap-1 activates p38MAPK module
is not fully elucidated, the findings that bg-pathway
can stimulate C3G (Mochizuki et al., 2000), and C3G
can stimulate Rap-1 (Gotoh et al., 1995) as well as
MLK3/DLK family of kinases (Tanaka and Hanafusa,
1998) and MLK3 can activate p38MAPK (Chadee and
Kyriakis, 2004; Kim et al., 2004) points to MLK family
of MAP3Ks as a possible link between Rap-1 and
Gaqstimulation of p38MAPKg/ERK6 module
p38MAPKg, an isoform of p38MAPK that shows
distinct expression and activation profiles, is character-
ized as ERK6 (Lechner et al., 1996; Kumar et al., 1997;
Wang et al., 2000). Similar to the p38MAPK module,
p38MAPKg/ERK6 is activated by the MAP2Ks,
MKK3 and MKK6 (Kumar et al., 1997; Wang et al.,
2000). It has also been shown that the small GTPase
Rho activates p38MAPKg/ERK6 via its stimulatory
interaction with PKN, which can activate the MLK-like
kinases that act as MAP3Ks of this module (Wang et al.,
2000; Gross et al., 2002; Takahashi et al., 2003). Initial
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
evidence that Gq-mediated pathways are involved in the
activation of p38MAPKg/ERK6 came from the obser-
demonstrated the activation of ERK6/p38MAPKg
in response to carbachol (Marinissen et al., 1999). In
analysing the role of PAR-1 receptors in stimulating
c-Jun expression and oncogenic transformation, the
ability of Gaq to activate p38MAPKg/ERK6 was
characterized. It appears that the activation of ERK6
is mediated primarily by the a-subunit rather than the
bg-subunit (Marinissen et al., 2003). Since Gaq can
associated Rho-GEF (LARG) (Booden et al., 2002), it
is very likely that Gaq-mediated activation of the
activation of PKN and subsequent stimulation of
MLK-family of MAP3Ks followed by MKK3/6 and
p38MAPKg/ERK6 (Wang et al., 2000; Marinissen et al.,
2001, 2003; Gross et al., 2002; Takahashi et al., 2003). In
this context, it should be noted that since p38MAPKg/
ERK6 is activated by MKK3 and MKK6, which are
also involved in the activation of other p38MAPK-
isoforms, it could also be regulated by the mechanisms
outlined in the previous section.
Gqstimulation of ERK5
Gq-mediated signaling has also been shown to regulate
the ERK-5 module via MEK5 (Marinissen et al., 1999).
Studies using the transient expression of Gq-coupled
muscarinic receptors have identified that the Gq-
mediated signaling pathway is involved in the regulation
of the MEK5–ERK-5 signaling module and subsequent
transactivation of c-Jun via MEF2 family of transcrip-
tion factors (Marinissen et al., 1999). Further studies
using a chimeric mutant of Gaqand Gai, through which
Gaq-mediated signaling can be activated by Gai-coupled
muscarinic receptors, have established that Gaqand not
Gbgqis involved in the activation of ERK5 (Fukuhara
et al., 2000b). Although the mechanism by which Gaqis
coupled to the MEK5–ERK5 module is not fully
understood, initial studies have identified that it is not
through Ras, CDC42, Rac or Rho (Fukuhara et al.,
2000b). However, the observation that the MAP3Ks
MEKK2 and MEKK3 can interact and activate MEK5
(Sun et al., 2001) suggests the possible role of these
MAP3Ks in this pathway. In conjunction with the
findings that Rap-1 is involved in the activation of
ERK5 via MEKK2 (Wang et al., 2006a) and Gqcan
activate Rap-1 via the Rap-1-GEF CG3 or CalDAG-
GEFI as discussed in the previous sections, it is likely
that Gaq, via Rap-1, activates the MEKK2–MEK5–
ERK5 module. However, these earlier events involved
in Gaq-mediated activation of ERK5 remain to be
Regulation of MAPKs by G12
The G12family of G proteins, defined by the a-subunits
Ga12 and Ga13, is extremely potent in inducing
neoplastic transformation of fibroblast cell lines (Chan
et al., 1993; Jiang et al., 1993; Xu et al., 1993; Vara
Prasad et al., 1994; Voyno-Yasenetskaya et al., 1994;
Dhanasekaran and Dermott, 1996; Liu et al., 1997). In
view of the findings that constitutively active Ga12was
isolated as the transforming ‘oncogene’ from the Ewings
sarcoma cell line (Chan et al., 1993) and that Ga12
potently stimulates the neoplastic transformation of
fibroblast cell lines (Chan et al., 1993; Jiang et al., 1993;
Xu et al., 1993; Vara Prasad et al., 1994; Voyno-
Yasenetskaya et al., 1994), it has been designated as
‘gep’ oncogene (Xu et al., 1994; Gutkind et al., 1998). In
addition, the expression of these a-subunits has been
shown to stimulate mitogenic responses in many
different cell lines (Aragay et al., 1995; Denis-Henriot
et al., 1998; Coffield et al., 2004). Further analyses have
revealed that these a-subunits can regulate cell prolife-
ration (Aragay et al., 1995; Denis-Henriot et al., 1998;
Radhika and Dhanasekaran, 2001; Coffield et al., 2004;
Kumar et al., 2006), differentiation (Jho and Malbon,
1997), apoptosis (Althoefer et al., 1997; Berestetskaya
et al., 1998), as well as cell migration (Offermanns et al.,
1997; Radhika et al., 2004; Dhanasekaran, 2006; Shan
et al., 2006) in a context-specific manner. A search for
the underlying signaling mechanism(s) identified that
G12proteins strongly stimulate JNK activity in a variety
of cells (Prasad et al., 1995; Collins et al., 1996; Voyno-
Yasenetskaya et al., 1996; Jho et al., 1997; Nagao et al.,
1999; Arai et al., 2003; Marinissen et al., 2003), and the
inhibition of which could abrogate Ga12/13-mediated G1
to Sphase cell cycle progression (Mitsui et al., 1997).
G12/13signaling to JNK module
Having 67% shared amino acid identity, Ga12and Ga13
stimulate similar responses including the activation of
JNK in many cellular contexts (Radhika and Dhanase-
karan, 2001). However, the mechanism through which
these a-subunits couple to the JNK module appears to
be cell-type or physiological context dependent. In these
different contexts, Ga12 and Ga13 activate the JNK
module via the small GTPases Ras, CDC42, Rac or Rho
(Figure 4). Although the activated mutant of Ga12
stimulates JNK via Ras in NIH3T3 cells, it involves
Rac1 in 1321N astrocytoma and HEK293 cells (Collins
et al., 1996). In Cos-7 cells, it has been shown to involve
CDC42 (Voyno-Yasenetskaya et al., 1996). All of these
small GTPases appear to transmit signals to the JNK
module via MEKK1, as the expression of dominant
negative MEKK1 has been shown to inhibit Ga12-
mediated activation of JNK in all of these instances
(Collins et al., 1996; Voyno-Yasenetskaya et al., 1996).
Thus, Ga12as well as Ga13communicates to MEKK1,
the upstream MAP3K of the module, via the Ras- or
Rho family of small GTPases, presumably through
specific GEFs. The identity of the specific GEFs that
couple Ga12or Ga13to JNK module has been identified
only in a few instances (Lee et al., 2004).
In the case of the Ras-GEF linking Ga12to Ras, it
appears to involve Shc-mediated recruitment of SOS
(Collins et al., 1997). It has been shown that Ga12
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
stimulates Shc-phosphorylation in 1321N1 cells, in
which it stimulates JNK via Ras-dependent mechanism
(Collins et al., 1996, 1997). Therefore, it has been
suggested that Shc-Grb2-recruited SOS is involved in
stimulating Ras and subsequently JNK in these cells
(Collins et al., 1997). Although the kinase involved in
stimulating the phosphorylation of Shc has not been
identified, considering the findings that Ga12 can
stimulate several tyrosine kinases such as Src (Nagao
et al., 1999), Fak (Needham and Rozengurt, 1998;
Chikumi et al., 2002) and Tec family of kinases (Mao
et al., 1998; Jiang et al., 1998), it possible that one of
these kinases may be involved in stimulating the
phosphorylation of Shc. In this context, the observa-
tions that Ga12can stimulate BTK, a member of Tec
family of kinases (Jiang et al., 1998) and BTK can
activate JNK via Shc-Grb2-mediated activation of Ras
(Deng et al., 1998), make BTK or one of its family
members an attractive candidate in this pathway. The
identities of the GEFs that link Ga12/13to downstream
Rac and CD42 are largely unknown.
In addition to Ras, Rac and CDC42, it has also been
shown that Ga12 stimulates JNK via RhoA (Nagao
et al., 1999; Arai et al., 2003). In HEK293 cells, it has
also been shown that Src-dependent stimulation of
RhoA is involved in Ga12-mediated activation of JNK
(Nagao et al., 1999). The findings that inhibition of Src
by treating the cells with PP2 or expressing the
dominant negative mutant of Src abrogated the ability
of Ga12to stimulate such activation suggested that an
Src-mediated GEF activity is involved in linking Ga12to
Rho-mediated activation of JNK module (Nagao et al.,
1999). Although the mechanism by which Ga12signals
to Src is not fully understood, the ability of Ga12to
stimulate the GEF activity of tyrosine-phosphorylated
LARG is quite significant (Fukuhara et al., 2000a;
Suzuki et al., 2003). LARG may thus be a candidate
Rho-GEF involved in linking Ga12to Rho in an Src-
dependent manner and subsequent activation of JNK
module. However, it is also possible that Ga12stimulates
Rho-mediated activation of JNK module via other Src-
responsive Rho-GEFs. In the case of Ga13, it has been
shown that it can physically interact with p115RhoGEF
and stimulate its GEF activity toward RhoA (Hart
et al., 1998). Consistent with this observation, Rho-
dependent activation of JNK has been shown to involve
p115RhoGEF in P19 cells (Lee et al., 2004). Notwith-
standing the small GTPase utilized, the MAP3K
involved in Ga12/13-mediated signaling appears to
involve MEKK1 (Collins et al., 1996; Voyno-Yasenets-
kaya et al., 1996; Wang et al., 2002). In some contexts,
the JNK module activated by Ga12/13involves ASK1
(Berestetskaya et al., 1998), MEKK-2 or MEKK4 as
well (Wang et al., 2002; Lee et al., 2004). Generally, the
MAP3Ks activate MKK4 as well as MKK7, the JNK-
specific MAP2Ks. However, it has been observed that
Ga12-mediated activation of JNK preferentially involves
MKK7 (Dermott et al., 2004), whereas Ga13- as well as
bg-mediated activation appears to involve MKK4
(Yamauchi et al., 1999; Wang et al., 2002; Lee et al.,
2004). Although, the functional significance of these
differential preferences for specific MKKs is largely not
known, it should be noted here that the dual specificity
kinases MKK4 and MKK7 activate JNK by phosphory-
lating two different amino acid residues. MKK4 has
been shown to preferentially phosphorylate Tyr185,
whereas MKK7 phosphorylates Thr187 of JNK1
(Fleming et al., 2000). It has been proposed that both
MKK4 and MKK7 are required for the maximal
activation of JNK1 (Yang et al., 1997; Lawler et al.,
1998; Lisnock et al., 2000). Since Ga12 appears to
preferentially stimulate MKK7 (Dermott et al., 2004),
whereas Ga13stimulates MKK4 (Wang et al., 2002; Lee
et al., 2004), it is likely that the Ga12- and Ga13-mediated
Rho family of GTPases. In some cells, Ga12/13can weakly stimulate ERK1/2 in a Ras-dependent manner, whereas in others they
attenuate ERK1/2 activation at the levels of MEKs. In addition, both Ga12 and Ga13 can activate ERK5 through hitherto
uncharacterized mechanism. In addition, Ga12and Ga13can regulate different MAPKs through pathways unique to them (dashed
lines). While Ga12inhibits p38MAPKs in some cell types at the levels of MKKs, Ga13stimulates p38MAPKs including p38MAPKg/
ERK6 via MKK3/6 in some cells.
G12/13regulation of MAPK networks. Ga12as well as Ga13can potently activate JNK module by stimulating Ras as well as
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
response requires only a partial activation of JNK from
the respective MAP2K signaling nodes. It is likely that
such partial activation of JNK along with other
signaling inputs, such as the activation of ERK module
and attenuation of p38MAPK module, are prerequisites
for Ga12-mediated cell proliferation of NIH3T3 cells or
Ga13-mediated P19 cell differentiation in which the
differential recruitment of MAP2Ks have been observed
(Dermott et al., 2004; Wang et al., 2002; Lee et al.,
Ga12/13attenuation of ERK1/2
In contrast to their potent activation of the JNK
module, Ga12 and Ga13 attenuate the activation of
ERK1/2 module in a cell-type-dependent manner
(Voyno-Yasenetskaya et al., 1996). Ras-mediated albeit
weaker stimulation of ERK1/2 has been shown to be
critically required – along with Ras-/Rac-mediated
potent stimulation of JNK activity – for Ga12-induced
G1–Sphase cell cycle progression of NIH3T3 cells
(Mitsui et al., 1997). However, the ectopic expression
of Ga12/13stimulated JNK activity with a concomitant
inhibition of ERK1/2 pathway (Voyno-Yasenetskaya
et al., 1996). Further analysis has identified MEK as the
locus at which Ga12/13exerts its inhibitory effects on
ERK module. Although the underlying mechanism as
well as the physiological significance of such regulation
is not fully known, recent studies have demonstrated
that Ga12/13 can interact with PP5 to stimulate its
activity (Yamaguchi et al., 2002) and PP5 is involved in
the downregulation of ERK module by dephosphory-
lating Raf-1 at Ser-338 (von Kriegsheim et al., 2006).
Therefore, although it remains to be established, it is
possible that Ga12/13-mediated activation of PP5 is
involved in the inhibition of ERK1/2 modules.
Inhibition of p38MAPK by Ga12
The expression of Ga12has also been shown to attenuate
the activation of the p38MAPK module (Dermott et al.,
2004). The inhibition was found to be at the level of the
three MAP2Ks involved in the activation of p38MAPK,
namely MKK4, MKK3 and MKK6. It is interesting
that Ga12stimulates JNK-specific MKK7 while inhibit-
ing MKK4, which is common to both JNK and
p38MAPK. Thus, Ga12appears to block decisively all
the possible signaling routes that lead to the activation
of p38MAPK. However, it should be noted here that the
inhibition of p38MAPK appears to be specific for Ga12
as the expression of Ga13in NIH3T3 cells stimulates
both JNK as well as p38MAPK activities (Marinissen
et al., 2003). Although the molecular basis for such
selective inhibition of an MAPK at the levels of multiple
MAP2Ks by distinct a-subunits of the G12family is not
clear at present, at least two possible mechanisms can be
speculated: one involving the inhibition of p38MAPK-
specific MKKs, presumably through the activation of a
specific phosphatase, and the other involving a specific
scaffolding protein that distinctly couples Ga12to the
MKK7–JNK module, while attenuating the MKK3/6/4-
p38MAPK module. Since Ga12 has been shown to
directly stimulate phosphatase PP5 (Yamaguchi et al.,
2002) as well as PP2A (Zhu et al., 2004), it is likely that
either or both of these phosphatases play a role in
attenuating p38MAPK module. However, such a role
for these proteins in Ga12-mediated attenuation of
p38MAPK module remains to be clarified. Likewise,
whether the downregulation of p38MAPK by Ga12is
seen in other cell types remain to be established.
However, such differential regulation of JNK and
p38MAPK modules is likely to have a significant role
in the potent mitogenic activity of Ga12seen in diverse
cell types (Chan et al., 1993; Jiang et al., 1993; Xu et al.,
1993; Vara Prasad et al., 1994; Voyno-Yasenetskaya
et al., 1994; Aragay et al., 1995; Dhanasekaran and
Dermott, 1996; Liu et al., 1997; Denis-Henriot et al.,
1998; Coffield et al., 2004). It is likely that the weak
stimulation of ERK activity and the decisive down-
regulation of p38MAPK in addition to the potent
stimulation of JNK module provide the multiple
signaling inputs required for Ga12-mediated cell pro-
Ga13stimulation of p38MAPg/ERK6
In contrast to Ga12, but similar to Gaq, Ga13has been
shown to stimulate the p38MAPKg/ERK6 module
(Marinissen et al., 2003). Considering the inhibitory
effect of Ga12on MKK3/MKK6, it is more likely that
Ga12exerts similar attenuation of p38MAPKg/ERK6,
at least in fibroblasts such as NIH3T3 cells. However,
the transient expression of Ga13 has been shown to
stimulate p38MAPKg/ERK6 activity in NIH3T3 as well
as HEK293 cells. It has been suggested that ERK6
stimulation of ATF2 and MEF2 is required for the
complete transactivation of c-Jun and the resulting
PAR-1 receptors (Marinissen et al., 2003). It has been
identified that Rho is involved in the upstream stimula-
tion of the ERK6 module via PKN family of protein
kinases (Marinissen et al., 2001, 2003). As Ga13 can
stimulate Rho via different GEFs, the mechanism by
which Ga13transmits signals to p38MAPKg/ERK6 is
likely to involve Rho and Rho-activated PKN. Since the
MAP3Ks such as MLK-like MAP triple kinase (Taka-
hashi et al., 2003) or MLK-related kinase (Gross et al.,
2002) can regulate ERK6 via MKK3/6 (Wang et al.,
2000; Marinissen et al., 2001, 2003; Gross et al., 2002;
Takahashi et al., 2003), it is likely that Ga13-activation
module involving these
Ga12/13stimulation of ERK5
In analysing the mechanism by which PAR-1 receptors,
which can couple to both Gq and G12-family of G
proteins, activate ERK5, it was identified that the
a-subunits of G12as well as G13are involved in the
regulation of ERK5. Since activation of ERK5 by
constitutively active Ga12and Ga13was insensitive to
the coexpression of the dominant negative mutants of
Ras, CDC42, Rac or Rho, the activation appears to
involve an alternate GTPase or mechanism (Fukuhara
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
et al., 2000b). An attractive candidate is Rap-1, which
can stimulate MEKK2 and hence the MEKK2–MEK5–
ERK5 module (Wang et al., 2006a). However this
possibility as well as the mechanism by which Ga12/13
communicates to Rap-1 needs to be experimentally
Receptor tyrosine kinases in G-protein-mediated
activation of MAPKs
In addition to the signaling pathways leading to the
regulation of MAPK modules by different G proteins,
GPCRs have been shown to regulate ERK1/2 modules
through the transactivation of RTKs. Such a novel role
for EGFR in the activation of ERK by GPCRs was
identified with the observation that the stimulation of
Rat1a cells with GPCR agonists including endothelin,
LPA and thrombin stimulated the phosphorylation of
EGFR and Her2 along with the activation of ERK2
(Daub et al., 1996). The findings that the treatment of
these cells with the EGFR inhibitor tyrphostin AG1478
or the expression of a dominant negative EGFR mutant
inhibited such ERK activation indicated the critical role
of EGFR in the activation of ERK by GPCRs (Daub
et al., 1996). Further analyses revealed that EGFR plays
a determinant role in GPCR-mediated activation of the
ERK module in a variety of cell types (Daub et al., 1997;
Zwick et al., 1997; Eguchi et al., 1998). Primarily, Gi-
and Gq-coupled receptors transactivate EGFR through
a novel mechanism involving ‘ecto-domain shedding’
and subsequent generation of soluble EGF-like growth
factors that can stimulate EGFRs (Prenzel et al., 1999).
Recently, the molecular basis for GPCR-mediated
transactivation of EGFR has been summarized (Ohtsu
et al., 2006). The transactivation of EGFR by GPCRs
involves both intracellular as well as extracellular
mechanisms. Thus, EGFR transactivation by Gi- or
Gq-coupled receptors has been shown to require the
intracellular generation of Ca2þ(Zwick et al., 1997;
Eguchi et al., 1998; Murasawa et al., 1998; Soltoff, 1998;
Iwasaki et al., 1999), and activation of PKC, Src and
Pyk2 (Gschwind et al., 2001). These pathways appear to
converge on the activation of a family of a disintegrin
and metalloprotease (ADAM) and/or matrix metallo-
protease (MMP) proteins through phosphorylation as
well as protein–protein interactions (Higashiyama and
Nanba, 2005; Ohtsu et al., 2006). The activated single
transmembrane ADAMs, specifically ADAM-10, -12,
-15, -17, cleave the ectodomains of membrane-bound
EGFR ligands such as HB-EGF to generate soluble
EGF ligands that can activate EGFRs (Gschwind et al.,
2001; Schafer et al., 2004; Higashiyama and Nanba,
2005; Ohtsu et al., 2006).
Although these studies have shown the role of EGFR
in G-protein signaling, it has also been shown that
signaling by RTKs to the ERK module can be enhanced
b-arrestin. For example, it has been shown that the
activation of the ERK module by RTK ligands involves
a G-protein-independent as well as G-protein-dependent
pathways (Conway et al., 1999). In the G-protein
independent, classical pathway, signaling to ERK
involves PDGF-activated PDGFR autophosphoryla-
tion on tyrosine residues, recruitment of adaptor
proteins and activation of p42/p44 MAPK. However,
the G-protein-dependent pathway appears to involve Gi
and b-arrestin-mediated endocytosis. In this pathway,
endocytitic internalization of Gi-activated GPCRs along
with Gi-activated c-Src, PDGFR, ERK module and
Grb-2 is facilitated by arrestin and dynamin II. It has
been speculated that the close proximity and the possible
activation of Raf-1 by Src promotes the activation of
ERK module in endosomes (Waters et al., 2005).
Further studies should define the role of such network-
ing between RTKs and G proteins in specific cellular
Scaffold proteins in G-protein signaling to MAPKs
As discussed in previous sections, diverse GPCRs,
through the a- as well as the bg-subunits of the four
classes of G proteins, modulate the activities of different
MAPK modules. Interestingly, as can be seen in the case
of PAR- or thrombin receptors, a specific GPCR may
recruit a- or bg-subunits from different classes of G
proteins to activate an MAPK module in a cell type- or
context-specific manner. Even the individual a- or bg-
subunit may activate a specific MAPK module through
more than one mechanism in a context-specific manner.
In addition, the signaling molecules providing these
mechanisms such as the small GTPase, their cognate
GEFs, and the downstream kinases, are often shared by
different Ga- or bg-subunits activating distinct MAPK
modules. So the major question is how do these distinct
pathways from different G proteins elicit distinct
functional responses involving specific MAPKs with
little or no signaling crosstalk with each other. Although
studies from yeast have pointed out that specific scaffold
proteins such as Ste5 can facilitate such context-specific
linking of G-protein signaling to downstream MAPK
modules (Herskowitz, 1995; Elion, 2001; Elion et al.,
2005), the evidence for such scaffold proteins in
mammalian G-protein signaling to MAPKs emerged
only recently. Of these scaffold proteins, some of them
such as the b-arrestins play a catalytic as well as
anchoring role in linking different GPCRs to MAPK
signaling, whereas others such as MAP kinase organizer
(MORG) and JLP play an anchoring role by tethering
specific G proteins and MAPK modules in a context-
specific manner (Garrington and Johnson, 1999; Morrison
and Davis, 2003; Kolch, 2005).
Catalytic role of b-arrestin in GPCR signaling to ERKs
The arrestin family of proteins was initially identified
to be involved in the desensitization of GPCRs
by facilitating their internalization (Freedman and
Lefkowitz, 1996; Kohout and Lefkowitz, 2003). Signaling
by agonist-activated GPCRs is terminated by the
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
GRK-family of serine/threonine kinases that phosphory-
late the receptors at their C-termini (Freedman and
Lefkowitz, 1996). b-arrestins bind to such phospho-
rylated receptors and facilitate their internalization
by endocytosis via clathrin-coated pits (Shenoy and
Lefkowitz, 2003). Interestingly, it has been shown that
b-arrestin-1 can bind to both GRK-phosphorylated
receptors, such b2-AR, as well as c-Src, targeting them
to clathrin-coated pits where the complex acts as
signaling hub for the activation of ERK1 and ERK2
(Luttrell et al., 1999). In addition, it has been shown that
b-arrestin-2 can sequester components of the ERK
module such as Raf-1, MEK1/2 and ERK1/2 via its
interaction with Raf-1 (Luttrell et al., 2001). The b-
arrestin scaffold containing the components of the ERK
module and the receptor are internalized via clathrin-
coated pits into endosomal vesicles where the receptor
can activate the ERK module (Lefkowitz and Shenoy,
2005). Although the mechanism by which the inter-
nalized GPCR can activate the ERK module is yet to
be elucidated fully, it is possible that the other
co-internalized intermediary molecules such as Src play
a role in providing such a link. Interestingly, it has been
noted that the ERK module activated by b-arrestin has
slower kinetics of activation than that mediated by G
proteins (Lefkowitz and Shenoy, 2005). In addition, it
has been observed that the ERK module activated by
b-arrestin is not involved in nuclear signaling (DeFea
et al., 2000; Tohgo et al., 2002). Thus, b-arrerestin-2-
mediated activation of ERK module by different
GPCRs appears to be involved in the cytosolic responses
that require slower but persistent activation of ERKs
(DeFea et al., 2000; Tohgo et al., 2002; Lefkowitz and
In addition to the activation of the ERK module,
b-arrestin-2 also appears to be involved in regulating
the JNK module. Using yeast two hybrid screening, it
was identified that b-arrestin-2 can interact with JNK3
(McDonald et al., 2000). Further analyses indicated that
b-arrestin-2 interacts with the MAP3K, ASK1. In
addition, MKK-4 also can be colocalized along with
b-arrestin, ASK1 and JNK3 in a complex. It has also
been observed that angiotensin II type IA receptor
stimulated the colocalization of b-arrestin-2 and JNK3
to intracellular vesicles along with the activation of
JNK3 (McDonald et al., 2000). However, it is not clear
whether b-arrestin plays a catalytic role in stimulating
JNK3 in this context.
Role of MORG-1 in linking GPCRs to ERK1/2 pathway
MORG-1 was identified as a 35kDa protein that
interacts with MEK-partner 1 proteins in a yeast two
hybrid screen (Vomastek et al., 2004). Further charac-
terization of this WD-40 motif containing protein
indicated that it can associate with Raf-1, B-Raf,
MEK1, MEK2, ERK1 and ERK2. Although the ectopic
expression of MORG1 enhanced LPA or PMA-
mediated activation of ERK, it failed to have such
stimulatory effects on PDGFR- or EGFR-mediated
activation of ERK. In addition, although silencing
MORG-1 suppressed ERK-1 activation by FBS (which
contains several ligands including LPA that can activate
the respective GPCRs), it did not have any effect on
EGF-stimulated ERK response. Thus, MORG-1 that
can associate with the MAP3K, MAP2K, as well as the
MAPK components of ERK1/2 module, appears to
provide a scaffolding function specifically for GPCRs
such as LPA receptors. At present, it is not known
whether such a role of MORG1 involves its physical
interaction with specific GPCRs, Ga- or Gbg-subunits.
Further studies should define the molecular mechanism
by which MORG-1 links GPCR signaling to ERK1/2.
Role of JLP in linking Ga12/13to JNK module
JLP was initially identified as a Leucine Zipper domain
containing protein that can interact with Max (Lee
et al., 2002). In addition, it has been observed that
JLP can interact with JNK, p38MAPK, MKK4
and MEKK3. Furthermore, it was observed that the
expression of JLP potentiated cytotoxic stress-mediated
activation of JNK (Lee et al., 2002). Recent studies have
shown that JLP can interact with Ga12as well as Ga13
and provide a scaffolding role for JNK activation by
these a-subunits (Kashef et al., 2005). It has been
demonstrated that JLP interacts with the a-subunits of
the G12family through the C-terminal region of JLP,
spanning amino acids 1165–1307. Using the expression
of this Ga12/13interacting domain or siRNA-mediated
silencing of JLP, it was demonstrated that the disruption
of the JLP–Ga13interaction leads to the attenuation of
LPA- as well as Ga13-mediated activation of JNK.
Furthermore, it has been observed that silencing JLP
inhibits retinoic acid-mediated endodermal differentia-
tion of P19 cells (Kashef et al., 2006), which is critically
dependent on Ga13-mediated activation of JNK (Jho
et al., 1997; Wang et al., 2002; Lee et al., 2004). In this
context, it is significant to note that JLP is the first
known mammalian scaffold protein, albeit similar to
Ste5, in tethering all the signaling components from the
proximal Ga-subunit to the downstream MAPK. Since
the Ga12/13-interacting C-terminus of JLP is conserved
among all the JIP family of scaffold proteins, it is
possible that JIPs may also be involved in linking Ga12/
13or other a-subunits to JNK or p38MAPK modules in
a context-specific manner. This, as well as other finer
details of the JLP scaffold, such as its interactions with
specific small GTPases and their GEFs, remains to be
established. Similarly, further studies should define the
role of such scaffold proteins in Ga- or Gbg-mediated
activation of other MAPK modules.
Recent studies have contributed to a greater under-
standing of the mechanisms by which the GPCR family
of cell surface receptors critically regulate different
aspects of cell growth via the MAPK signaling modules.
As the signaling nexus between different G proteins
and distinct MAPK modules are being realized, the
G Proteins and MAPKs
ZG Goldsmith and DN Dhanasekaran
pathophysiological roles of aberrant- or asynchronous
signaling by these pathways are becoming increasingly
clear. However, as presented in this review, several
aspects of these pathways involved in G-protein-
mediated MAPK activation remain to be resolved.
For example, the molecular basis for context-specific
signaling, the spatio-temporal organization of G-protein–
MAPK signaling complexes, the effects of these path-
ways in relation to receptor tyrosine kinase- or cytokine
receptor-mediated activation of MAPKs, and most
importantly, the potential role of G-protein-regulated
MAPK networks in tumorigenesis and progression
remain to be fully characterized. A case to the point is
the identification of the potential role of LPA- and
PAR-receptor-mediated signaling pathways in the gene-
sis and progression of ovarian, breast and prostate
cancers (Mills and Moolenaar, 2003; Booden et al.,
2004; Daaka, 2004; Boire et al., 2005). The findings that
all of these GPCRs, their cognate G proteins and the G-
protein oncogenes gsp, gip2 and gep converge on the
activation of distinct MAPK modules, taken together
with the observation that GPCR-mediated signaling
pathways are well-validated drug targets, underscore
the critical need for defining these pathways further so
that better therapeutic targets can be identified.
The study was supported by a grant from NIH (GM 49897).
Critical reading of the paper by Dr Rashmi Kumar and
Mr Jake Gardner are gratefully acknowledged.
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