When a G protein-coupled receptor does not couple to a G protein

Sun, Yutong; McGarrigle, Deirdre; Huang, Xin

doi:10.1039/b706343a

Cited by 74 publications

(46 citation statements)

References 54 publications

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“…Surprisingly, it has been recently proposed that some GPCRs do not couple to G proteins and then are able to activate ERK1/2 by a G protein-independent signaling. In M a n u s c r i p t 10 fact, Jak/STATs, Src-family tyrosine kinases, GRKs/β-arrestins, and PDZ domaincontaining proteins have been suggested to relay signals from GPCRs, independent of G proteins, which could result in ERK1/2 activation (Sun et al, 2007). The single report on MC5R signaling states that this receptor activates the Jak/STAT pathway on Blymphocytes (Buggy, 1998) but the involvement of the ERK1/2 signaling cascade is not referred.…”

Section: Discussionmentioning

confidence: 99%

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Rodrigues

Pignatelli

Almeida

et al. 2009

Molecular and Cellular Endocrinology

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receptor activates ERK1/2 through a PI3K-regulated signaling mechanism. Molecular and Cellular Endocrinology, Elsevier, 2009, 303 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t SummaryMelanocortin 5 receptor (MC5R) is a G-protein coupled receptor (GPCR) with high affinity for α-MSH. To unravel some of the downstream cell-signaling pathways activated by this receptor, HEK293 cells were transiently and stably transfected with a vector encoding green fluorescent protein (GFP)-tagged MC5R. In these cells the receptor was correctly addressed to the cell surface and was functional, as shown by the MC5R-induced formation of intracellular cAMP. In fact, the MC5R agonist α-MSH induced a 10 or 16 fold increase (transient or stable cells, respectively) above the cAMP levels found in unstimulated cells. Moreover, in cells stably expressing MC5R-GFP, α-MSH promoted ERK1/2 phosphorylation in a dose-dependent manner (EC50=7.3nM) with the maximal effect occurring after 5min of agonist incubation. The signaling pathway conveyed through ERK1/2 is not linked to cAMP, since the phosphorylation of these kinases is unchanged by the inhibition of adenylyl cyclase. Also, ERK1/2 activation is not significantly affected by PKA, PKC and Akt/PKB specific inhibitors. However, α-MSH-induced ERK1/2 activation is abolished by the PI3K inhibitors wortmannin and LY294002. Altogether, these findings demonstrate that MC5R signals through a PI3K-regulated Akt-independent pathway leading to downstream activation of ERK1/2. The involvement of these MAPK suggests that MC5R could be implicated in cellular proliferation or differentiation mechanisms.

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Section: Discussionmentioning

confidence: 99%

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Rodrigues

Pignatelli

Almeida

et al. 2009

Molecular and Cellular Endocrinology

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“…The implication is that b-arrestin is able to recruit Src kinase as part of a larger scaffold which, following ligand binding, allows the activation of the kinase by b-arrestin. Furthermore, it has also been suggested that the b2AR can interact directly with Src kinase to facilitate delayed activation of the MAPK pathway (Huang et al, 2004;Sun et al, 2007).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

CXCL12 receptor preference, signal transduction, biological response and the expression of 5T4 oncofoetal glycoprotein

McGinn

Marinov

Sawan

et al. 2012

Journal of Cell Science

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SummaryCXCL12 is a pleiotropic chemokine capable of eliciting multiple signal transduction cascades and functions, via interaction with either CXCR4 or CXCR7. Factors that determine CXCL12 receptor preference, intracellular signalling route and biological response are poorly understood but are of central importance in the context of therapeutic intervention of the CXCL12 axis in multiple disease states. We have recently demonstrated that 5T4 oncofoetal glycoprotein facilitates functional CXCR4 expression leading to CXCL12 mediated chemotaxis in mouse embryonic cells. Using wild type (WT) and 5T4 knockout (5T4KO) murine embryonic fibroblasts (MEFs), we now show that CXCL12 binding to CXCR4 activates both the ERK and AKT pathways within minutes, but while these pathways are intact, they are non-functional in 5T4KO cells treated with CXCL12. Importantly, in the absence of 5T4 expression, CXCR7 is upregulated and becomes the predominant receptor for CXCL12, activating a distinct signal transduction pathway with slower kinetics involving transactivation of the epidermal growth factor receptor (EGFR), eliciting proliferation rather than chemotaxis. Thus the surface expression of 5T4 marks the use of the CXCR4 rather than the CXCR7 receptor, with distinct consequences for CXCL12 exposure, relevant to the spread and growth of a tumour. Consistent with this hypothesis, we have identified human small cell lung carcinoma cells with similar 5T4/CXCR7 reciprocity that is predictive of biological response to CXCL12 and determined that 5T4 expression is required for functional chemotaxis in these cells.

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“…In addition, just as there is heterogeneity in the G protein array available for 7TMR interaction, there are data to suggest that ␤-arrestin is functionally diverse as well (Shukla et al, 2008). Finally, it should be noted that 7TMR signaling and behavior can also be mediated by other cytosolic proteins in addition to G proteins and ␤-arrestin (Bockaert and Pin, 1999;Heuss and Gerber, 2000;Brady and Limbird, 2002;Bockaert et al, 2004;Lanier, 2004;Gavarini et al, 2006;Sun et al, 2007b). Current data for agonist bias most often report effects seen with synthetic agonists, but there is at least one 7TMR in which it is operative for natural ligands.…”

Section: Operational Mechanisms Of Functional Selectivity a Historimentioning

confidence: 99%

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

2010

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When a G protein-coupled receptor does not couple to a G protein

Cited by 74 publications

References 54 publications

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

Melanocortin 5 receptor activates ERK1/2 through a PI3K-regulated signaling mechanism

CXCL12 receptor preference, signal transduction, biological response and the expression of 5T4 oncofoetal glycoprotein

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

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