Linkage of G Protein-Coupled Receptors to the MAPK Signaling Pathway Through PI 3-Kinase γ

López-Ilasaca, Marco; Crespo, Piero; Pellici, P. Giuseppe; Gutkind, J. Silvio; Wetzker, Reinhard

doi:10.1126/science.275.5298.394

Cited by 646 publications

(586 citation statements)

References 17 publications

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“…In other cell types, the ability of G protein-coupled receptors to activate the p101/p110c form of PI3K (class Ib or PI3Kg) is known to involve bc subunits. Interestingly, overexpression of PI3Kc in COS-7 cells resulted in MAPK activation in a bc-dependent manner and expression of a mutated enzyme lacking lipid kinase activity abolished these responses [138]. This study also noted that stimulation of MAPK by PI3Kc required a tyrosine kinase which phosphorylated the adaptor Shc, causing its association with Grb2 and activation of Ras.…”

Section: Activation Of Phosphoinositide 3-kinasesupporting

confidence: 52%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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Chronic persistent asthma is characterized by poorly reversible airflow obstruction and airways inflammation and remodelling. Histopathological studies of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result of hyperplastic and/or hypertrophic growth, is believed to be one of the principal contributors to airway wall thickening. In recent years, significant advances have been made in elucidating the mediators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent airflow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversible phenotypic modulation and increased heterogeneity of airway smooth muscle function may also be a feature of the asthmatic airway. This review focuses on possible mechanisms controlling smooth muscle phenotype heterogeneity as well as on the mediators and intracellular pathways implicated in its cellular proliferation. Particular attention is paid to mechanisms involving activation of the extracellular signal regulated kinase‐, protein kinase C‐ and phosphoinositide 3‐kinase‐dependent pathways, since these appear to be the major candidate second messenger pathways for G protein‐ and tyrosine kinase‐coupled receptor‐stimulated proliferation.

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Section: Activation Of Phosphoinositide 3-kinasesupporting

confidence: 52%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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“…Several studies have reported that MAPK activation by G ␤␥ is mediated by phosphatidyl inositol-3-kinase (PI3K), and that tyrosine kinases may also play a role in the G ␤␥ pathway (Crespo et al, 1994;Lopez-Ilasaca et al, 1997;Lopez-Ilasaca, 1998). Specific inhibitors of PI3K and tyrosine kinases were thus tested for their ability to inhibit carbachol activation of MAPK in astrocytoma cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Most studies have investigated the effects of M 1 or M 3 receptors, either endogenously expressed or transfected into various cell types (Tournier et al, 1994;Quian et al, 1995;Haring et al, 1998;Larocca and Almazan, 1997;Budd et al, 1999;Rosenblum et al, 2000;Slack, 2000). There is also evidence that M 2 muscarinic receptors can stimulate MAPK, through the G ␤␥ subunit (Crespo et al, 1994;Lopez-Ilasaca et al, 1997). In case of M 2 receptors, the signaling to MAPK appears to involve Ras and phosphatidylinositol 3-kinase (PI3K) (Crespo et al, 1994;Lopez-Ilasaca et al, 1997), while for the other subtypes, an involvement of protein kinase C (PKC) has been suggested, albeit with contrasting results (Kim et al, 1999;Budd et al, 1999;Keely et al, 1998;Haring et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…There is also evidence that M 2 muscarinic receptors can stimulate MAPK, through the G ␤␥ subunit (Crespo et al, 1994;Lopez-Ilasaca et al, 1997). In case of M 2 receptors, the signaling to MAPK appears to involve Ras and phosphatidylinositol 3-kinase (PI3K) (Crespo et al, 1994;Lopez-Ilasaca et al, 1997), while for the other subtypes, an involvement of protein kinase C (PKC) has been suggested, albeit with contrasting results (Kim et al, 1999;Budd et al, 1999;Keely et al, 1998;Haring et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

Yagle

Guizzetti

et al. 2001

Glia

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Mitogen-activated protein kinase (MAPK) can be phosphorylated by mitogens binding to G-protein-coupled receptors and is considered a major pathway involved in cell proliferation. In this study, we report on the activation of MAPK by muscarinic acetylcholine receptors in astroglial cells, namely the 1321N1 human astrocytoma cell line, primary rat cortical astrocytes, and fetal human astrocytes. Carbachol caused a rapid and transient phorphorylation of MAPK (ERK1/2) in all cell types, with an increase in MAPK activity, without changing the levels of MAPK proteins. Human astrocytoma cells were used to characterize the effect of carbachol on MAPK. Experiments with M 2 -and M 3 -receptor subtype-selective antagonists, and with pertussis toxin, indicated that the M 3 subtype is responsible for activating MAPK in glial cells. Pretreatment of cells with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, or downregulation of PKC by 24-h treatment with the phorbol ester TPA inhibited carbachol-induced MAPK activation. Additional experiments with PKC ␣-or PKC ⑀-specific compounds indicated that the ⑀ isozyme of PKC is primarily involved in MAPK activation by carbachol. Chelation of calcium also inhibited MAPK activation by carbachol. Two MEK (MAPK kinase) inhibitors inhibited carbacholinduced DNA synthesis but only at concentrations that exceeded those sufficient to block carbachol-induced MAPK activation. Ethanol (Յ200 mM) had no effect on MAPK when present alone and did not affect carbachol-induced MAPK activation under various experimental conditions, although it inhibits carbachol-induced DNA synthesis at low concentrations (10-100 mM). These results suggest that activation of MAPK by carbachol may be necessary but not sufficient for its mitogenic effect in astroglial cells, and that does not represent a target for ethanol-induced inhibition of DNA synthesis elicited by muscarinic receptors. GLIA 35:111-120, 2001.

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“…The molecular basis for such speci®city is currently unknown and it represents an important issue that needs to be addressed. PI3Kg has been described as an important mediator of cell responses initiated by heterotrimeric GTP-binding protein-coupled receptor (GPCR) including the activation of the serine/threonine MAP kinases (MAPK) (Lopez-Ilasaca et al, 1997). Considering the important role for MAPK in the induction of DNA synthesis (Graves et al, 1995), one would predict a function for PI3Kg in cell growth as induced by GPCR.…”

Section: Introductionmentioning

confidence: 99%

A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells

2000

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Linkage of G Protein-Coupled Receptors to the MAPK Signaling Pathway Through PI 3-Kinase γ

Cited by 646 publications

References 17 publications

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells

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