Oncogene (2001) 20, 1601 ± 1606
ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00
www.nature.com/onc
G protein coupled receptor signaling through the Src and Stat3 pathway:
role in proliferation and transformation
Prahlad T Ram*,1 and Ravi Iyengar1
1
Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029, USA
Extracellular signals when routed through signaling
pathways that use heterotrimeric G proteins can
engage multiple signaling pathways leading to diverse
biological consequences. One locus at which signal
sorting occurs is at the level of G proteins. G protein
a-subunits appear to be capable of interacting with
di€erent e€ectors leading to engagement of distinct
signaling pathways. Regulation of di€erent pathways
in turn leads to di€erent biological outcomes. The
process of neoplastic transformation is controlled to a
large extent through the activation and inhibition of
signaling pathways. Signaling pathways such as the
Ras-MAPK, v-Src-Stat3 pathways are activated in the
process of transformation. Expression of activated Ga
subunits have been shown to cause transformation of
cells. While activation of the MAPK 1,2 pathway by
various Ga subunits has been reported for several
years, recent studies show the activation and involvement of Src and Stat3 pathways in Gao and Gai
mediated transformation of cells. Recent studies also
suggest that both Gai and Gas may be able to
interact with and activate Src. The activation of Src
and Stat3 by G proteins has also been demonstrated
by ligand-induced activation of G protein receptors.
So increasingly it is becoming clear that the Src and
Stat3 pathways are potential e€ectors for G proteins
and that they may play a role in G protein function.
Oncogene (2001) 20, 1601 ± 1606.
Keywords: G protein
transformation
alpha
subunit;
Src;
Stat3;
Introduction
Signal transduction pathways activated by G proteins
have been studied for a number of years. The classical
G protein signaling pathway that was identi®ed very
early on was the activation of the adenylyl cyclasecAMP pathway by Gas (Gilman, 1987). Subsequently
the inhibition of adenylyl cyclase by the Gai subunit
was determined. Since these early discoveries several
other Ga subunits as well as several isoforms of Gb
and Gg subunits have been characterized. The Ga
subunits can be broadly classi®ed into four families:
the Gas family including Gas, Gaolf, and a
*Correspondence: PT Ram
transducin; the Gai family which includes Gai, Gao
and Gaz; the Gaq/Ga11 family; and the Ga12/13
family. As these new Ga subunits were identi®ed the
e€ectors pathways for these subunits were sought out,
and over the years a number of e€ector pathways such
as the PLC, Rho/Cdc42 pathways, and the Ca2+
channels have been identi®ed (Buhl et al., 1995;
Diverse-Pierluissi, 1995; €rench-Mullen et al., 1994;
Taylor et al., 1990). In addition to activation of
second messenger molecules, Ga subunits can also
modulate the activity of transcription factors, thereby
regulating gene expression (Corre et al., 1999; Fan et
al., 2000; Montminy, 1997; Ram et al., 2000). So
signaling by G protein coupled receptors is not just
limited to second messenger molecules but also
includes transcription factors and molecules that a€ect
the cytoskeleton. Discovering the full array of downstream e€ectors for G proteins is an ongoing process
that will continue to yield new and exciting information.
Recently the activation of Stat3 by members of
the Gai family, particularly Gao and Gai2 has
been identi®ed (Corre et al., 1999; Ram et al.,
2000). Additionally others have also reported the
ligand-induced activation of Stat's via activation of
G protein coupled receptors (Liang et al., 1999;
Marrero et al., 1995). The activation of the Stat
pathway by Ga subunits appears to be mediated
via Src. The modulation of a transcriptional
cofactor by Gaz has also been reported (Fan et
al., 2000). Taken together with the classical
Gas?cAMP?PKA?CREB pathway it appears
that in addition to regulation of cytoplasmic and
membrane functions Ga subunits also regulate gene
expression.
The role of G protein a subunits in the neoplastic
transformation of cells has been studied for a number
of years. Expression of activated Gao, ai2, aq, a12, and
a13, has been shown to cause transformation of cells
(Jiang et al., 1993; Kalinec et al., 1992; Kroll et al.,
1992; Pace et al., 1991; Vara Prasad et al., 1994).
Additionally expression of constitutively activated G
protein receptors have also been shown to cause
transformation of cells (Allen et al., 1991; Arvanitakis
et al., 1997; Cesarman et al., 1996) Therefore, understanding the signaling mechanism leading to the
transformation of cells by G protein a subunits and
G protein coupled receptor pathways will be very
important.
G protein regulation of Src and Stat's in transformation
PT Ram and R Iyengar
1602
E€ectors for Gao and Gai2
Among the Ga subunits, the Gao subunit has been
more dicult to study in terms of e€ector regulation.
Gao belongs to the Gai family of G protein a subunits
and shares about an 82% homology with Gai and is
pertussis toxin sensitive (Neer et al., 1984; Sternweis
and Robishaw, 1984; Van Meurs et al., 1987). The
tissue distribution of Gao is quite interesting in that
Gao is abundantly expressed in neuronal tissue
(Gierschik et al., 1986). Intracellularly, Gao is found
localized in the growth cones of neuronal tissue,
suggesting a role for Gao in neuronal function (Nusse
and Neer, 1996). The constitutively activated Gao in
which Gln 205 is changed to Leu (Q205L), thereby
resulting in a mutant Gao subunit which lacks
guanosine triphosphatase (GTPase) activity, has
greatly aided in the analysis of Gao function.
Expression of activated Gao in Xenopus oocytes
triggers the oocyte to re-enter the cell cycle through
the protein kinase C, c-mos dependent pathway (Kroll
et al., 1991). Expression of activated Gao results in the
transformation of NIH3T3 cells (Kroll et al., 1992),
and it has also been demonstrated that expression of
Gao in PC-12 cells results in increased neurite
outgrowth (Strittmatter et al., 1994). Gao has also
been shown to play a role in vesicle release in
chroman cells (Ohara-Imaizumi et al., 1992; Sontag
et al., 1991) and modulation of Ca2+ channels in chick
dorsal root ganglion (DRG) neurons (Diverse-Pierluissi
et al., 1997). While these physiological readouts have
been observed for several years the downstream
signaling mechanisms by which Gao regulates these
functions were not well understood.
Over the years a few downstream e€ectors of Gao
have been discovered. The PLC/PKC pathway has
been found to be activated during Xenopus germinal
vesicle breakdown (Kroll et al., 1991), and the Src
tyrosine kinase pathways in the activation of Ca2+
channels in chick DRG neurons (Diverse-Pierluissi et
al., 1997). The signaling pathways involved in the Gao
induced transformation of NIH3T3 have been shown
to be by the Src and the Stat3 pathways (Ram et al.,
2000). Direct binding partners of Gao include Rap1GAP and GRIN (Chen et al., 1999; Jordan et al.,
1999)
The role of the Gai subunit in transformation has
been observed for several years. Gai2 has been
implicated in ovarian and pituitary tumors (Lyons et
al., 1990). The mutant form of Gai2, which is thought
to be oncogenic, was termed gip2 and was found to be
over expressed in a small subset of ovarian tumors
(Lyons et al., 1990), however this does not appear to
be widespread as other populations of ovarian tumors
have failed to show expression of gip2 (Shen et al.,
1996). Expression of Gai2 in Rat-1 cells results in
increased proliferation and transformation of cells
(Pace et al., 1991). Additionally expression of dominant negative Gai2 has been shown to inhibit
melanoma cell proliferation (Hermouet et al., 1996).
Recent data shows that Gai2 like Gao activates c-Src
Oncogene
and Stat3 in the transformation of cells (Corre et al.,
1999) these data suggest that Gai2 as well Gao can
play a role in the proliferation of cells. Their role in
cell proliferation may be quite important in tumors of
neuroendocrine origin such as in melanomas, where
both Gai2 and Stat3 have been shown to regulate
proliferation and transformation (Hermouet et al.,
1996; Niu et al., 1999).
Role of Src and Stat3 in oncogenesis
c-Src is a member of a family of cytoplasmic tyrosine
kinases that are involved in many biological processes
(Thomas and Brugge, 1997). Activities of the src family
of kinases have been implicated in proliferation,
migration and di€erentiation. The src family members
are 52 ± 62 kDa proteins that have several domains
including a catalytic domain, a regulatory domain, and
SH2 and SH3 binding domains (Thomas and Brugge,
1997). c-Src in its inactive form is phosphorylated at
Tyr-527 and interacts with its own SH2 domain, thus
masking its catalytic domain (Brown and Cooper,
1996). Upon activation c-Src is dephosphorylated at
Tyr-527 and no longer interacts with its own SH2
domain, resulting in a conformational change which
then activates its catalytic domain (Brown and Cooper,
1996). Activated c-Src is then capable of interacting
with and activating several substrates. Data from
several labs have shown that both v-Src and c-Src
are capable of activating Stat3 in ®broblasts (Bromberg
et al., 1998; Turkson et al., 1999; Yu et al., 1995).
The signal transducers and activators of transcription (Stat) family of proteins are implicated in the
functions of a wide range of cells (Akira, 2000;
Bromberg and Darnell, 2000). Stat proteins are
activated in response to several cytokines and growth
factors. The classical example of Stat activation is via
the interluekin/gp130 receptor, which is activated by Il6. Il-6 binding activates the receptor leading to
recruitment of Janus kinases (Jak's). Jak activation
then results in binding, phosphorylation and activation
of Stats. When phosphorylated Stat3 is activated, it
dimerizes, and translocates to the nucleus where it
binds DNA and modulates gene expression (Schindler
and Darnell, 1995). Receptor tyrosine kinases (RTK)
such as PDGF-R and EGF-R also activate Stat3
(Zhong et al., 1994). Stat3 has been implicated in the
neoplastic transformation of several cell types, and
transformation of NIH3T3 and mammary epithelial
cells by the oncogene v-src is dependent on Stat3
activation (Bowman et al., 2000; Bromberg et al., 1998;
Smith and Crompton, 1998), and further, expression of
constitutively activated Stat3 itself results in transformation (Bromberg et al., 1999). MAPKinase 1,2 can
phosphorylate Ser727 on Stat3 and phosphorylation of
this residue is thought to modulate the transcriptional
activity of Stat3 (Chung et al., 1997). Additionally,
activation of p38 and JNK/SAPK is thought to be
required for v-Src activation of Stat3 (Turkson et al.,
1999).
G protein regulation of Src and Stat's in transformation
PT Ram and R Iyengar
G protein coupled receptor mediated activation of Stat's
G protein coupled receptors (GPCRs) are cell surface
receptors that are activated by hormones and neurotransmitters. Activation of the angiotensin II (AT1)
receptor has also been shown to phosphorylate Stats 1,
2 and 3 (Liang et al., 1999; Marrero et al., 1995).
Additionally melanocyte stimulating hormone (MSH)
binding and activating the melanocortin receptors has
also been shown to activate Stats in B-lymphocytes
(Buggy, 1998). In addition to ligand induced activation
of GPCR's several groups have identi®ed mutant
GPCRs that are constitutively activated (Arvanitakis
et al., 1997; Cesarman et al., 1996). When these mutant
receptors are expressed in NIH3T3 cells they result in
increased proliferation and in the transformation of the
cells. Mutant active melanocortin receptor has been
identi®ed (Robbins et al., 1993) and it is quite possible
that mutant active GPCR's that are expressed in vivo
may activate Src and Stat3 leading to changes in the
normal physiology of the cell. Therefore activation of
Stat's by G protein coupled receptor pathways may be
physiologically relevant for both proliferation and
di€erentiation.
Gene expression by Gao and Gai through Src and Stat3
Gao and Gai2 mediated transformation of ®broblasts
both signal via the Src and Stat3 pathway and this
discovery was simultaneously made by Hermout and
colleagues as well as in our laboratory (Figure 1)
(Corre et al., 1999; Ram et al., 2000). Expression of
Q205L Gao in NIH3T3 cells results in increased
proliferation and the transformation of the cells
(Ram et al., 2000). Expression of Q205L Gao increases
endogenous c-Src activity, and expression of CSK
inhibits Gao mediated cell proliferation. Gao also
increased Tyr705 phosphorylation of Stat3 as well
increased Stat3 transcriptional activity. Expression of
dominant negative Y705F Stat3 inhibited Gao
mediated Stat3 activity. Further both CSK and
Y705F Stat3 were able to inhibit Gao mediated
transformation of NIH3T3 cells. The signaling mechanism of Gai2 mediated transformation is also
regulated through the Src and Sta3 pathway (Corre
et al., 1999). Hermout and colleagues have shown that
expression of dominant negative mutant of Gai2
inhibits v-fms mediated transformation of ®broblasts.
Further dominant negative Gai2 inhibited both Src and
Stat3 activities.
In addition to the regulation of Stat3 mediated
transcription activity another member of the Gai
family Gaz is also able to regulate transcriptional
activity. Both Gaz and Gai modulates transcription
activity by directly binding to the Eya2 transcription
co-factor, sequestering it in the cytoplasm thereby
decreasing the transcriptional activity of the Six/Eye2
transcription factor (Fan et al., 2000). These data show
that Gao/i/z subunits are able to regulate transcriptional activities in addition to second messenger
signaling pathways.
1603
Role of small G proteins in Src and Stat3 signaling
A step in the pathway of activation of Src and Stat3
appears to involve small GTPases such as Ras, Rac-1,
Rap-1 and Ral-1 (Ceresa et al., 1997; Goi et al., 2000;
Simon et al., 2000). The di€erent small G proteins may
Figure 1 Pathways involved in mediating Gao activation of Stat3. Activation of Stat3 by Gao and Gai2 subunits in ®broblasts is
mediated by Src activation. The mechanism of Src activation by Gao is currently not known. Downstream from Src, activation of
Stat3 may be dependent on activation of JNK and/or the p38 kinases
Oncogene
G protein regulation of Src and Stat's in transformation
PT Ram and R Iyengar
1604
be either upstream or downstream of Src (Goi et al.,
2000; Xing et al., 2000). The role of Ras signaling in
Stat3 activation has been demonstrated for a number
of years, whereby Ras activation of MAPK 1, 2 and
the subsequent MAPK 1, 2 phosphorylation of Stat3
may be required for Stat3 activity (Herrmann et al.,
1996). Another small G protein, Rac-1, has also been
demonstrated to be involved both in the IL-6
activation of Stat3 (Schuringa et al., 2000) as well as
in v-Src mediated activation of Stat3 (Turkson et al.,
1999). Recent data suggests the Rac-1 directly interacts
with Stat3 leading to phosphorylation and activation
of Stat3 (Simon et al., 2000). In addition to Ras and
Rac involvement in Src and Stat3 signaling another
small G protein, Ral-1, has been implicated in the
EGF-R mediated activation of Src and Stat3 (Goi et
al., 2000). Additionally c-Src activation induced by Sin
and Cas (SH3 domain containing multiadapter proteins) is mediated by Rap-1 (Xing et al., 2000). Thus it
appears likely that small G proteins may play an
important role in signaling networks by acting as signal
integrators by connecting di€erent pathways.
Figure 2 Model of a possible signaling complex mediating Ga activation of Stat3. Direct interactions between Ga and Src, Src and
Stat3, and Rac and Stat3 has been reported (see text). p38 is also be necessary for Stat3 activation by Src. While a sca€old for Rac
and p38 has not yet been identi®ed, it is possible that one exists, since sca€olds for two other members of the MAPK family
(MAPK 1, 2 and JNK) have been identi®ed
Figure 3 Alternate mechanism of Gao activation of Src. Gao subunits may utilize the small G proteins Rap1 and Ral1 to activate
Src. Rap1-GAP has been identi®ed as a direct interacting protein for Gao. Rap1 in turn has been reported to activate Ral1, via
Ral1-GEF in some cell lines. Ral1 in turn has been shown to mediate Src and subsequently Stat3 activation
Oncogene
G protein regulation of Src and Stat's in transformation
PT Ram and R Iyengar
Mechanism of Gao and Gai signaling to Src and Stat3
Conclusion
transformation, is evidence that understanding the
signaling mechanism leading to neoplastic transformation by the Ga subunits is important. Elucidating the
exact signaling mechanism leading from Ga subunits to
the activation of downstream signaling e€ectors such
as Src and Stat3 is ongoing. Several studies have shown
the direct binding of many if the signaling components
in a pair-wise manner, leading to the activation of
Stat3. Whether all these components can come together
in a large complex is not known. Also not clear is the
role of the small G proteins and where along the
signaling pathway they function since small G protein
signaling can occur both upstream and downstream of
Src. The role of the di€erent MAPkinases in Stat3
signaling is also not clearly known. From the published
reports thus far it appears that both small G proteins
and MAPkinases do play a role in Stat3 activation and
some reports even suggest an essential role for these
signaling molecules leading to Stat3 activity. Clearly
from all reports Stat3 plays an important role in
proliferation and transformation of cells. In cells where
endogenous Gao or Gai are expressed, activation of
GPCR's that couple to them could lead to activation
of Stat3 and changes in gene expression. This may be
an important pathway in neurons where Gao activation can lead to neurite outgrowth and neuronal
plasticity.
As we discover new signaling pathways that are
modulated by G proteins it is becoming apparent that
GPCR mediated signaling utilizes several di€erent
signaling pathways. Understanding the mechanism of
signal sorting and integration between these di€erent
signaling pathways and networks, and their role in
physiological processes, is fast becoming an important
facet of modern biological research. Using the data
from single signaling pathways and building up
complex signaling networks we can gain a systems
understanding of the behavior and the physiological
outcome given speci®c stimuli. Gaining a systems
understanding will be of great use for the design of
strategies and molecules by which speci®c points in the
signaling network can be modulated, thereby leading to
speci®c changes in the physiological endpoint.
G protein coupled receptors are capable of activating
multiple signaling pathways and modulating several
physiological processes. The role of Ga subunits in the
transformation of cells has been investigated for several
years. The discovery of mutant GPCR's that couple to
Ga subunits, that have been shown to cause
Acknowledgments
PT Ram was supported by an NIH post-doctoral fellowship F32 CA79134. Parts of the work described here are
supported by NIH grants GM54508 and CA81050 to R
Iyengar.
The mechanism of activation of Src by Ga subunits
may be direct. A recent report by Huang and
colleagues suggests that Gai and Gas are both able
to directly bind Src, leading to its activation (Ma et al.,
2000). However using co-immunoprecipitation experiments we have been unable to see interactions between
Gao and endogenous c-Src in NIH3T3 cells (unpublished observation). How Gao activates c-Src is not yet
known. Downstream from Src, data suggests that Stat3
and Src may also directly bind, leading to Stat3
phosphorylation and activation (Cao et al., 1996). In
addition to direct Src and Stat3 binding recent work by
Guan and colleagues show that Rac-1 and Stat3 are
also direct binding partners (Simon et al., 2000). Taken
together with the data that the downstream signaling
molecules of Rac-1 such as p38 and JNK are necessary
for activation of Stat3 (Schuringa et al., 2000; Turkson
et al., 1999; Uddin et al., 2000), it is possible that all
these signaling molecules may come together in a large
complex ultimately leading to Stat3 activation this
speculative model is shown in Figure 2.
An alternate mechanism of activation of Src and
Stat3 by Gao and Gai2 may exist through the Rap-1
and Ral pathways (Figure 3). In this paradigm the
direct binding partner for Gao, Rap-1-Gap, modulates
the activity of Rap-1 (Jordan et al., 1999) which in turn
can modulate the activity of Ral-1 (Herrmann et al.,
1996; Bos, 1998), Ral-1 in turn has been shown to
activate Src and subsequently Stat3 (Goi et al., 2000).
A third possible mechanism of activation of Src by
Gao may occur through an indirect mechanism of
activating metalloproteinases thereby leading to cleavage of proHB-EGF and ligand induced activation of
EGF-R (Prenzel et al., 1999) and the subsequent
activation of Src and Stat3. This pathway may be
speci®c for EGF and may not occur in all cell types. It
remains to be determined if any of these mechanisms
are used for Gao activation of c-Src.
1605
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