Genetic analysis of mammalian G-protein signalling

Offermanns, Stefan; Simon, Melvin I.

doi:10.1038/sj.onc.1202173

Cited by 44 publications

(37 citation statements)

References 38 publications

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“…activating adenylyl cyclases) highly related to G␣olf. Such compensatory mechanisms have previously been observed between G␣ subunits (Offermanns and Simon, 1998).…”

Section: Research Articlesupporting

confidence: 64%

Adenylyl cyclase-dependent axonal targeting in the olfactory system

et al. 2007

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The vertebrate olfactory bulb is a remarkably organized neuronal structure, in which hundreds of functionally different sensory inputs are organized into a highly stereotyped topographical map. How this wiring is achieved is not yet understood. Here, we show that the olfactory bulb topographical map is modified in adenylyl cyclase 3 (adenylate cyclase 3)-deficient mice. In these mutants, axonal projection targets corresponding to specific odorant receptors are disorganized, are no longer exclusively innervated by functionally identical axonal projections and shift dramatically along the anteroposterior axis of the olfactory bulb. Moreover, the cyclase depletion leads to the prevention of neuropilin 1 (Nrp1) expression in olfactory sensory neuron axonal projections. Taken together, our data point to a major role played by a crucial element of the odorant-induced transduction cascade, adenylyl cyclase 3, in the targeting of olfactory sensory neuron axons towards the brain. This mechanism probably involves the regulation of receptor genes known to be crucial in axonal guidance processes.

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“…activating adenylyl cyclases) highly related to G␣olf. Such compensatory mechanisms have previously been observed between G␣ subunits (Offermanns and Simon, 1998).…”

Section: Research Articlesupporting

confidence: 64%

Adenylyl cyclase-dependent axonal targeting in the olfactory system

et al. 2007

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“…Surprisingly, G␣ 11 , even though expressed at levels similar to those of other G proteins, was most potent in stimulating the ERK cascade. Considering the high degree of redundancy of G q and G 11 in signal transduction (23,46), further studies are needed to judge whether the apparently stronger ERK activation by G 11 reflects a property that distinguishes it from G q in vivo. However, we cannot entirely exclude that slight differences in the expression levels of G proteins or an increased apoptosis induced by some constitutive active mutants (15) might also have an impact on their ability to activate ERK in these assays.…”

Section: Discussionmentioning

confidence: 99%

G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Gα_q and Gα_i Signals

Blaukat

Barac

Cross

et al. 2000

Molecular and Cellular Biology

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103

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G protein-coupled receptors (GPCRs) have been shown to stimulate extracellular regulated kinases (ERKs) through a number of linear pathways that are initiated by G q/11 or G i proteins. We studied signaling to the ERK cascade by receptors that simultaneously activate both G protein subfamilies. In HEK293T cells, bradykinin B 2 receptor (B 2 R)-induced stimulation of ERK2 and transcriptional activity of Elk1 are dependent on G␣ qmediated protein kinase C (PKC) and on G␣ i -induced Ras activation, while they are independent of G␤␥ subunits, phosphatidylinositol 3-kinase, and tyrosine kinases. Similar results were obtained with m 1 and m 3 muscarinic receptors in HEK293T cells and with the B 2 R in human and mouse fibroblasts, indicating a general mechanism in signaling toward the ERK cascade. Furthermore, the bradykinin-induced activation of ERK is strongly reduced in G␣ q/11 -deficient fibroblasts. In addition, we found that constitutively active mutants of G␣ q/11 or G␣ i proteins alone poorly stimulate ERK2, whereas a combination of both led to synergistic effects. We conclude that dually coupled GPCRs require a cooperation of G␣ i -and G q/11 -mediated pathways for efficient stimulation of the ERK cascade. Cooperative signaling by multiple G proteins thus might represent a novel concept implicated in the regulation of cellular responses by GPCRs.The family of G-protein-coupled receptors (GPCRs) is the largest and most complex group of integral membrane proteins involved in signal transduction. These receptors can be activated by a diverse array of external stimuli, including growth factors, vasoactive peptides, chemoattractants, neurotransmitters, hormones, phospholipids, photons, odorants, and taste ligands. Following ligand binding they promote the GDP-GTP exchange of heterotrimeric G proteins. In turn, GTP-bound ␣ subunits and released ␤␥ complexes initiate a broad range of intracellular signaling events, including the activation of classical effectors such as adenylyl cyclases, phosphodiesterases, and phospholipases and the regulation of the activity of ion channels, ion transporters, and several kinases (22,23,41,59). Recently, it has become increasingly apparent that, like receptor tyrosine kinases, GPCRs and G proteins are also involved in the regulation of cell growth and differentiation. A number of human proliferative diseases have been linked to mutations of GPCRs or G proteins (5, 15, 16). Furthermore, overexpression of constitutively active GPCRs or G proteins, as well as prolonged agonist stimulation of GPCRs, can induce cellular transformation in cultured fibroblasts (2,15,25).The question of how GPCRs control signals that regulate gene expression in the nucleus, even though intensively studied during the last years, is not yet fully answered. It has been shown that GPCRs can activate mitogen-activated kinase (MAPK) pathways, which is sufficient and necessary for the control of proliferation in different cellular systems (26,39). Mechanisms by which GPCRs activate MAPK cascades appear to be diff...

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“…6,13,14 In the present study, we investigated the function of the peripheral cannabinoid receptor when overexpressed on myeloid cells (ie, 32D/G-CSF-R [granulocyte colony-stimulating factor receptor]) in which we overexpressed exon-1B/exon-2 Cb2 splice variant and a myeloid leukemia cell line containing a virus insertion in the Cb2 locus, NFS 78. We also wished to determine which of the large panel of Cb2 ligands that have been identified previously is the true agonist of the receptor.…”

mentioning

confidence: 99%

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

Jordà

Verbakel

Valk

et al. 2002

Blood

147

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Cb2 is a novel protooncogene encoding the peripheral cannabinoid receptor. Previous studies demonstrated that 2 distinct noncoding first exons exist: exon-1A and exon-1B, which both splice to proteincoding exon-2. We demonstrate that in retrovirally induced murine myeloid leukemia cells with proviral insertion in Cb2, exon-1B/exon-2 Cb2 messenger RNA levels have been increased, resulting in high receptor numbers. In myeloid leukemia cells without virus insertion in this locus, low levels of only exon-1A/exon-2 Cb2 transcripts were present and receptors could not be detected. To elucidate the function of Cb2 in myeloid leukemia cells, a set of in vitro experiments was carried out using 32D/G-CSF-R (granulocyte colony-stimulating factor receptor) cells transfected with exon-1B/exon-2 Cb2 complementary DNA and a myeloid cell line carrying a virus insertion in Cb2 (ie, NFS 78). We demonstrate that a major function of the Cb2 receptor is stimulation of migration as determined in a transwell assay. The cannabinoid receptors belong to the superfamily of 7-transmembrane G protein-coupled receptors (GPCRs). Several GPCRs have been shown to be involved in cell growth and oncogenesis as the result of aberrant expression. [5][6][7] Examples of GPCRs with transforming ability are the ␣1B-adrenergic, 8 thrombin, 9 and serotonin 1c receptors 10 and the receptor encoded by MAS oncogene. 11,12 Our previous observation that Cb2 is a common virus integration site suggests that aberrant expression of this 7-transmembrane receptor may be a critical event in transformation in certain cases of leukemia. 3 The protein-coding region of Cb2 is located on a single exon (exon-2) of approximately 4 kilobases. Recently we identified 2 distinct 5Ј noncoding exons (ie, exon-1A and exon-1B) previously designated exon-1 and exon-1Ј, respectively. 3 In the study presented here we first carried out experiments to investigate Cb2 messenger RNA (mRNA) transcripts and protein expression in leukemic cells with or without retroviral insertion in the Cb2 locus. Secondly, we performed studies to determine the function of the peripheral cannabinoid receptor when overexpressed in myeloid cells.GPCRs have been related to many functions, including cell proliferation, maturation, survival, apoptosis, or migration. 6,13,14 In the present study, we investigated the function of the peripheral cannabinoid receptor when overexpressed on myeloid cells (ie, 32D/G-CSF-R [granulocyte colony-stimulating factor receptor]) in which we overexpressed exon-1B/exon-2 Cb2 splice variant and a myeloid leukemia cell line containing a virus insertion in the Cb2 locus, NFS 78. We also wished to determine which of the large panel of Cb2 ligands that have been identified previously is the true agonist of the receptor. We investigated the effects of natural (␦ 8 24 ) cannabinoids. We show that 2-AG is the most potent agonist for the Cb2 receptor and that a major function of 2-AG is stimulation of migration. We further studied whether 2-AG acts as a chemotactic or chemokinetic age...

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Genetic analysis of mammalian G-protein signalling

Cited by 44 publications

References 38 publications

Adenylyl cyclase-dependent axonal targeting in the olfactory system

Adenylyl cyclase-dependent axonal targeting in the olfactory system

G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Gα_q and Gα_i Signals

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

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Genetic analysis of mammalian G-protein signalling

Cited by 44 publications

References 38 publications

Adenylyl cyclase-dependent axonal targeting in the olfactory system

Adenylyl cyclase-dependent axonal targeting in the olfactory system

G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Gαq and Gαi Signals

Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol

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G Protein-Coupled Receptor-Mediated Mitogen-Activated Protein Kinase Activation through Cooperation of Gα_q and Gα_i Signals