Trends in Pharmacological Sciences
ReviewG-protein-coupled receptors and signaling networks: emerging paradigms
Section snippets
G proteins and GPCRs in normal cell growth and cancer
Many potent mitogens such as thrombin, lysophosphatidic acid (LPA), bombesin, vasopressin, bradykinin, substance K, acetylcholine receptor agonists, angiotensin II and others stimulate cell proliferation by acting on their cognate GPCRs in a variety of cell types 4, 5, 6. The discovery of the mas oncogene, whose protein product exhibits a typical heptahelical structure, provided a link between cellular transformation and GPCRs (Ref. 7). No activating mutations were found in mas but instead the
A network of MAPKs links GPCRs to the nucleus and beyond
Recent work has revealed that multiple intracellular signaling pathways mediate the proliferative effects of GPCRs. Among them, a family of closely related proline-targeted serine–threonine kinases, collectively known as extracellular signal-regulated kinases (ERKs) or MAPKs, appears to play a central role. Following phosphorylation by their immediate upstream MEK, members of the MAPK family translocate to the nucleus where they phosphorylate transcription factors, thereby regulating the
G-protein-independent signaling by heptahelical receptors
Several recent provocative reports have revealed that GPCRs can interact with a wide variety of intracellular molecules in addition to heterotrimeric G proteins, thus broadening the molecular mechanisms by which these receptors transduce environmental signals. For example, the adaptor molecule arrestin binds many phosphorylated GPCRs and is primarily involved in targeting these receptors for endocytosis. However, arrestin has also been shown to couple GPCRs to the activation of Src-like kinases
Conclusions: unraveling the complexity of GPCR-mediated signaling pathways
The complexity of the molecular mechanisms whereby GPCRs transduce environmental signals has just begun to be fully appreciated. For a long time, the study of GPCR signaling has been focused on classical second-messenger-generating systems. However, we now realize that these intracellular signaling molecules are not sufficient to explain their wide array of biological responses. Instead, each GPCR would be expected to stimulate not one but a large number of highly interconnected cytoplasmic
References (76)
Modelling G-protein-coupled receptors for drug design
Biochim. Biophys. Acta
(1999)Orphan G protein-coupled receptors: a neglected opportunity for pioneer drug discovery
Trends Pharmacol. Sci.
(1997)Mitogenic action of lysophosphatidic acid
Adv. Cancer Res.
(1991)Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains
Cell
(1986)Calcium-induced activation of a mutant G-protein-coupled receptor causes in vitro transformation of NIH/3T3 cells
Neoplasia
(1999)- et al.
Molecular piracy of mammalian interleukin-8 receptor type B by herpesvirus saimiri
J. Biol. Chem.
(1993) Gα12 and Gα13 stimulate Rho-dependent stress fiber formation and focal adhesion assembly
J. Biol. Chem.
(1995)A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho
J. Biol. Chem.
(1999)Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G12 family to Rho
FEBS Lett.
(2000)The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades
J. Biol. Chem.
(1998)
Protein tyrosine phosphorylation induced by lysophosphatidic acid in Rat-1 fibroblasts. Evidence that phosphorylation of map kinase is mediated by the Gi-p21ras pathway
J. Biol. Chem.
Role of c-Src tyrosine kinase in G protein-coupled receptor- and Gβγ subunit-mediated activation of mitogen-activated protein kinases
J. Biol. Chem.
Role of arrestins in endocytosis and signaling of α2-adrenergic receptor subtypes
J. Biol. Chem.
Src tyrosine kinase is a novel direct effector of G proteins
Cell
Direct binding of activated c-Src to the β3-adrenergic receptor is required for MAP kinase activation
J. Biol. Chem.
Gβγ subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation
J. Biol. Chem.
The β2-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor
J. Biol. Chem.
A novel role for phosphatidylinositol 3-kinase β in signaling from G protein-coupled receptors to Akt
J. Biol. Chem.
Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak
Curr. Biol.
The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway
Cell
Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades
J. Biol. Chem.
Divergent signaling pathways link focal adhesion kinase to mitogen-activated protein kinase cascades. Evidence for a role of paxillin in c-jun NH(2)-terminal kinase activation
J. Biol. Chem.
Regulation of apoptosis by alpha-subunits of G12 and G13 proteins via apoptosis signal-regulating kinase-1
J. Biol. Chem.
Signal transduction by the JNK group of MAP kinases
Cell
The p38 signal transduction pathway: activation and function
Cell Signal
Activation of p38 mitogen-activated protein kinase by signaling through G protein-coupled receptors. Involvement of Gβγ and Gαq/11 subunits
J. Biol Chem.
Involvement of protein kinase C and Src family tyrosine kinase in Gαq/11-induced activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase
J. Biol. Chem.
Signaling from G protein-coupled receptors to ERK5/Big MAPK 1 involves Gαq and Gα 12/13 families of heterotrimeric G proteins. Evidence for the existence of a novel Ras and Rho-independent pathway
J. Biol. Chem.
Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases
Mol. Cell
G protein-coupled receptors: functional and mechanistic insights through altered gene expression
Physiol. Rev.
Early signals in the mitogenic response
Science
Cell growth control by G protein-coupled receptors: from signal transduction to signal integration
Oncogene
Ectopic expression of the serotonin 1c receptor and the triggering of malignant transformation
Science
Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes
Proc. Natl. Acad. Sci. U. S. A.
G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the α1B-adrenergic receptor enhances mitogenesis and tumorigenicity
Proc. Natl. Acad. Sci. U. S. A.
Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas
Nature
A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty
Nature
Mutations in G proteins and G protein-coupled receptors in endocrine disease
J. Clin. Endocrinol. Metab.
Cited by (872)
Cascaded amplifying circuit enables sensitive detection of fungal pathogens
2024, Biosensors and BioelectronicsUp-regulation of GPR139 in the medial septum ameliorates cognitive impairment in two mouse models of Alzheimer's disease
2024, International ImmunopharmacologyInnate functions of natural products: A promising path for the identification of novel therapeutics
2023, European Journal of Medicinal ChemistryAuriculocondylar syndrome: Pathogenesis, clinical manifestations and surgical therapies
2023, Journal of the Formosan Medical AssociationBreast carcinogenesis induced by organophosphorous pesticides
2023, Advances in Pharmacology