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
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