Therapeutic potential of β-arrestin- and G protein-biased agonists

Whalen, Erin J.; Rajagopal, Sudarshan; Lefkowitz, Robert J.

doi:10.1016/j.molmed.2010.11.004

Cited by 475 publications

(462 citation statements)

References 243 publications

Supporting

Mentioning

456

Contrasting

Unclassified

Order By: Relevance

“…In other words, RSPOs may be biased ligands for the Wnt pathway. Over the last decade, a variety of biased GPCR ligand have been discovered that selectively activate either G proteins or β-arrestins (Whalen et al, 2011). For example, CCL3, CCL4, CCL5, and CCL3L1, four different CCR5 ligands, show a relative bias for the processes of inositol-1-phosphate production and CCR5 internalization.…”

Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

View full text Add to dashboard Cite

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach.LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα 12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G 12/13 signaling.

show abstract

Section: Resultsmentioning

confidence: 99%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

View full text Add to dashboard Cite

show abstract

“…Of current therapeutic interest is the development of GPCR ligands that specifically activate G protein-dependent signaling pathways and not β-arrestin-dependent responses, and vice versa (4,26). The hope is that these selective or biased agonists will promote therapeutically beneficial signaling while curtailing cellular responses that adversely affect the patient.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the β-arrestins function as signal transducers themselves by coupling activated GPCRs to components of other signaling pathways, such as the MAPK cascade. The recent discovery of receptor ligands that preferentially activate G protein-dependent signaling over β-arrestin-dependent signaling, or vice versa, holds promise for the development of drugs with improved therapeutic efficacy and/or reduced side effects (4).…”

mentioning

confidence: 99%

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Oakley

Revollo

Cidlowski

2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin-dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs.

show abstract

“…Both conformational change and phosphorylation increase the affinity of the receptor for a small family of multifunctional GPCR regulatory or adaptor proteins known as the b-arrestins (ARRBs), including two superfamily members b-arrestin1 (ARRB1) and b-arrestin2 (ARRB2). This association blocks subsequent G protein activation and has an important role in traditional GPCR desensitization 19 . Several members of the GPCR family, including GPCR kinase-2 (GRK2) and ARRBs, have been implicated in the TNF-a-related inflammatory reaction 20,21 .…”

mentioning

confidence: 99%

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

et al. 2015

View full text Add to dashboard Cite

G-protein-coupled receptors (GPCR) constitute the largest known superfamily for signal transduction and transmission, and they control a variety of physiological and pathological processes. GPCR adaptor b-arrestins (ARRBs) play a role in cancerous proliferation. However, the effect of ARRBs in inflammation-mediated hepatocellular carcinogenesis is unknown. Here we show that ARRB1, but not ARRB2, is upregulated in inflammation-associated hepatocellular carcinoma (HCC) and paracancerous tissues in humans. A genotoxic carcinogen, diethylnitrosamine (DEN), significantly induces hepatic inflammation, TNF-a production and ARRB1 expression. Although ARRB1 deficiency does not affect hepatic inflammation and TNF-a production, it markedly represses hepatocellular carcinogenesis by suppressing malignant proliferation in DEN-treated mice. Furthermore, TNF-a directly induces hepatic ARRB1 expression and enhances ARRB1 interaction with Akt by binding to boost Akt phosphorylation, resulting in malignant proliferation of liver cells. Our data suggest that ARRB1 enhances hepatocellular carcinogenesis by inflammation-mediated Akt signalling and that ARRB1 may be a potential therapeutic target for HCC.

show abstract

Therapeutic potential of β-arrestin- and G protein-biased agonists

Cited by 475 publications

References 243 publications

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

Contact Info

Product

Resources

About