CST Guide:

Section I: Research Areas
chapter 02: Signaling
G Protein-Coupled Receptor Signaling: Overview
RhoA
β-Arrestin
AP2
clathrin
Receptor
Internalization
β-Arrestin
PI3K
Akt
Examples
Src
Ras
Raf
Erk
All GPCRs
p90RSK
Bad
M1, H1,
V2R, OXTR,
AT 1 R, PAR
Gα q
GDP
Gα q
GTP
β,γ
β,γ
GRK
GPR55, SDF-1,
PAR, S1P
Gα 12/13 β,γ
GDP
Gα 12/13
GTP
β,γ
β1-Adrenergic R
Wnt Ligand/Frizzled
Gα s
GDP
Gα s
GTP
β,γ
β,γ
CXCR4,
GABA-B, LPA
Gα i β,γ
GDP
Gα i β,γ
GTP
MMPs
VEGFR, PDGFR,
EGFR
Transactivation
Src
PI3K
Ion
Channels
Stat3
PLCβ PKC Rac RhoA Axin AC
CDC42 PI3K PLCβ
Ras
[cAMP]
CDC42
IP3
PAK
Akt
Raf
PKA
DAG
ROCK LATS1/2 GSK-3β
Ca 2+
SOS
MLK WASP
PAK
PKC
JNK p38 β-catenin CREB
GSK-3 Erk
Ras
Glycogen and
Actin
Fatty Acid
JNK
Remodeling
Synthesis
LATS1/2
Raf
Bad mTOR IKK
Survival Protein
Bcl-2
Synthesis
YAP/TAZ
p53
Inactive
NF-κB
RTK
G Protein-Coupled Receptor Signaling to MAP Kinase/Erk
Gi-Coupled
Receptor
Dynamin
G i
βγ
PLCβ
β-Arrestin GRK2
Src
PI3Kγ
Receptor
Internalization
endosome
H+
JNK3
Focal Adhesions
Catecholamines
MP
Src-like
Src c-Raf
β-Arrestin1 MEK
Erk
C-TAK1
TH
PKC
RTKs
IMP
Src
GRB2
RasGEF
SOS
Ras
GAP
MEK1/2
KSR
Src
FAK
Gα
PLCβ q
PYK2
GTP
RACK1
IP 3
[Ca 2+ ]
PKC
Ras
c-Raf
Erk1/2
Integrins
Ras
GRP
CaMKII,-IV
Ras
GRF
c-Raf B-Raf
Heterodimer
Gq-Coupled
Receptor
Syn
GAP
RGS
EPAC
Rap1
B-Raf
DUSP6
cPLA 2
Synapsins
AC
Gα s
GTP
[cAMP]
PKA
Gs-Coupled
Receptor
RGS
Bcl-xL
Erk
YAP/TAZ
Cytoplasm
Erk1/2 p90RSK
PEA-15
p90RSK
cdc25
c-Myc
p53
c-Fos
c-Jun
YAP/TAZ
G protein-coupled receptors (GPCRs), also known as 7-transmembrane receptors (7-TMR), form the largest family of cell membrane receptors with over 800 members.
GPCRs transmit extracellular signals initiated by ligands such as neurotransmitters, hormones, chemokines, and various lipid mediators to the cell interior through coupling to
heterotrimeric G proteins. G proteins consist of a GDP-bound Gα subunit complexed to β and γ subunits. Upon ligand binding, the α subunit exchanges GDP for GTP, causing
Gα activation, dissociation from the β/γ subunits, and initiation of signaling pathways that regulate numerous cellular responses, including proliferation, apoptosis, and cytoskeletal
rearrangements. There are four classes of Gα proteins, each with a unique signaling profile: Gαs, Gαi, Gαq, and Gα12/13. Gαs-coupled receptors activate adenylate
cyclase, generating cAMP and signaling through PKA . Gαi-coupled receptors inhibit AC and activate CDC42 and PI3K/Akt. Gαq signals through phospholipase C β (PLCβ),
Rac, and RhoA to regulate cell proliferation and survival by MAPK pathways and actin remodeling via Rock. Gα12/13 activates RhoA, leading to cytoskeletal rearrangements
as well as activation of the JNK, p38, and Hippo pathways. The β/γ subunits, particularly those associated with Gαi, can initiate signaling independent of Gα proteins, resulting
in regulation of Akt, PLCβ, and various ion channels. In certain cell types, GPCRs can transactivate receptor tyrosine kinases (RTKs) such as EGFR, PDGFR, and VEGFR,
thereby activating classical pathways of cell proliferation and survival. Termination of GPCR signaling occurs through phosphorylation by GPCR kinases (GRKs) and binding of
β-arrestin proteins, which leads to clathrin-mediated receptor internalization and degradation or recycling. β-arrestins can also propagate signals independent of Gα proteins,
initiating MAPK/Erk, Akt, and RhoA pathways.
Select Reviews:
Audet, M. and Bouvier, M. (2012) Cell 151, 14−23. • Entschladen, F., Zänker, K.S., and Powe, D.G. (2011) Cell Cycle 10, 1086−1091. • Kahn, S.M., Sleno, R., Gora, S.
et al. (2013) Pharmacol. Rev. 65, 545–577. • Lappano, R. and Maggiolini, M. (2012) Acta. Pharmacol. Sin. 33, 351−362. • Lappano, R. and Maggiolini, M. (2011) Nat.
Rev. Drug Discov. 10, 47−60. • O’Havre, M., Degese, M.S., and Gutkind, J.S. (2014) Curr. Opin. Cell Biol. 27C, 126−135. • Raiagopal, S., Raiagopal, K., and Lefkowitz,
R.J. (2010) Nat. Rev. Drug Discov. 9, 373−386. • Shukla, A.K., Xiao, K., and Lefkowitz, R.J. (2011) Trends Biochem. Sci. 36, 457−469. • Smrcka, A.V. (2008) Cell. Mol.
Life Sci. 65, 2191−2214. • Yu, F.X. and Guan, K.L. (2013) Genes Dev. 27, 355−371.
CREB
NF-κB
Erk
Nucleus
Nucleus
p90RSK
Transcription
Erk1/2
FoxO3
Tumorigenesis
MSK1/2
MAPKAPK2
Progression
of Cell Cycle
G protein-coupled receptors (GPCRs) are activated by a wide variety of external stimuli. Upon receptor activation, the G protein exchanges GDP for GTP, causing the dissociation
of the GTP-bound α and β/γ subunits and triggering diverse signaling cascades. Receptors coupled to different heterotrimeric G protein subtypes can utilize different scaffolds
to activate the small G protein/ MAPK cascade, employing at least three different classes of Tyr kinases. Src family kinases are recruited following activation of PI3Kγ by β/γ
subunits. They are also recruited by receptor internalization, crossactivation of receptor Tyr kinases, or by signaling through an integrin scaffold involving Pyk2 and/or FAK.
GPCRs can also employ PLCβ to mediate activation of PKC and CaMKII, which can have either stimulatory or inhibitory consequences for the downstream MAPK pathway.
Select Reviews:
Aoki, Y., Niihori, T., Narumi, Y., Kure, S., and Matsubara, Y. (2008) Hum. Mutat. 29, 992–1006. • Caunt, C.J., Finch, A.R., Sedgley, K.R., and McArdle, C.A. (2006) Trends
Endocrinol. Metab. 17, 276–283. • Goldsmith, Z.G. and Dhanasekaran, D.N. (2007) Oncogene 26, 3122–3142. • Kim, E.K. and Choi, E.J. (2010) Biochim. Biophys. Acta.
1802, 396–405. • McKay, M.M. and Morrison, D.K. (2007) Oncogene 26, 3113–3121.
© 2014–2015 Cell Signaling Technology, Inc. • We would like to thank Dr. Jonathan Violin, Trevena Inc., King of Prussia, PA for reviewing this diagram.
78 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
© 2002–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. John Blenis, Harvard Medical School, Boston, MA, for reviewing this diagram.
www.cellsignal.com/cstpathways 79