Arrestins: Introducing Signaling Bias Into Multifunctional Proteins

Gurevich, Vsevolod V.; Chen, Qiuyan; Gurevich, Eugenia V.

doi:10.1016/bs.pmbts.2018.07.007

Cited by 6 publications

(3 citation statements)

References 95 publications

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“…In addition, upon activation of β2-AR, PKA mediates β2-AR phosphorylation activating two major signaling pathways: Gβγ/PI3K/Akt and Ras/Raf/ MEK/ERK, which are involved in the occurrence and infiltration of HCC [31][32][33]. Meanwhile, the studies suggested that β2-AR mediated cAMP/PKA/ERK1/2 signaling promotes the growth of liver cancer cells [34]. In combination with the current study, the results showed that the ratios of p-ERK/ERK and p-Akt/Akt were significantly higher in DEN-induced HCC mice and in terbutaline-stimulated LX-2 cells.…”

Section: Discussionmentioning

confidence: 99%

β-arrestin2 regulating β2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression

Li¹,

Peng²,

Shan³

et al. 2021

J. Cancer

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Background: β-arrestin2 and β2-adrenergic receptor (β2-AR) have important roles in malignant tumors, the present study aims to investigate the role of activated β2-AR in hepatic stellate cells (HSCs) during hepatocellular carcinoma (HCC) progression and the regulatory effect of β-arrestin2. Methods: Immunofluorescence and Western blot were used to detect the expression of β-arrestin2 and β2-AR in HSCs of liver tissues from human HCC samples and diethylnitrosamine (DEN)-induced HCC model mice. We next used β-arrestin2 -/- mice to demonstrate the regulatory role of β-arrestin2 in DEN mice. The subsets of T cells were quantified by flow cytometry. MTT and wound healing assay were applied to detect the proliferation and migration of cells. Co-immunoprecipitation assay was used to detect the link of β-arrestin2 and β2-AR in HSCs. Effect of β-arrestin2 overexpression on β2-AR downstream signaling pathway was verified by Western blot. The secretion of CCL2 was detected by ELISA. Results: The expression of β2-AR was significantly increased, while β-arrestin2 was decreased in HSCs of HCC tissues. And β-arrestin2 deficiency exacerbates DEN-induced HCC accompanied with increased β2-AR expression. The results of flow cytometry showed that the percentage of activated T cells decreased gradually after DEN injection. β-arrestin2 knockout down-regulated the ratio of activated T cells. In vitro , selective activation of β2-AR in HSCs promoted the proliferation and migration of HCC cells. β-arrestin2 overexpression enhanced co-immunoprecipitation of β-arrestin2 and β2-AR in activated HSCs, and decreased its downstream Akt phosphorylation. Akt inhibitor decreased secretion of CCL2 in activated HSCs. Conclusion: Our study demonstrated that β2-AR activation in HSCs induces the proliferation and migration of HCC cells may be through Akt signaling, and this effect appears to be regulated by β-arrestin2.

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Section: Discussionmentioning

confidence: 99%

β-arrestin2 regulating β2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression

Li¹,

Peng²,

Shan³

et al. 2021

J. Cancer

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“…Arrestins have two major functions in GPCR regulation. First, receptor desensitization and internalization through recruitment of clathrin-coated pits [ 64 , 65 ] and second, the recruitment and activation of effectors such as MAPK and SFKs ([ 63 ] and reviewed in [ 66 , 67 ]). However, the concept of purely arrestin-based signaling has been recently challenged [ 68 ].…”

Section: Src Activation Through a Gpcr–arrestin Complexmentioning

confidence: 99%

New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation

Berndt

Liebscher

2021

IJMS

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Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)-mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much is known of their contribution to different signaling pathways. The suggested direct interaction between a GPCR and a SFK could allow for a potential immediate allosteric regulation of SFKs by GPCRs and thereby unravel a novel mechanism of SFK signaling. This overview will help to identify new GPCR–SFK interactions, which could serve to explain biological functions or be used to modulate downstream effectors.

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“…Two arrestin subtypes were found to be expressed in the retina, arrestin-1 and -4. These arrestins are specialized in binding light-activated phosphorylated rhodopsin and suppressing G protein activation [200,201]. It has been demonstrated that retinal and nonretinal arrestins mediate suppression of GPCRs, suggesting a common mechanism for desensitizing ARs [202].…”

Section: Role Of β-Ars In the Retinamentioning

confidence: 99%

The Role of Adrenoceptors in the Retina

Ruan

Böhmer

Jiang

et al. 2020

Cells

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The retina is a part of the central nervous system, a thin multilayer with neuronal lamination, responsible for detecting, preprocessing, and sending visual information to the brain. Many retinal diseases are characterized by hemodynamic perturbations and neurodegeneration leading to vision loss and reduced quality of life. Since catecholamines and respective bindings sites have been characterized in the retina, we systematically reviewed the literature with regard to retinal expression, distribution and function of alpha1 (α1)-, alpha2 (α2)-, and beta (β)-adrenoceptors (ARs). Moreover, we discuss the role of the individual adrenoceptors as targets for the treatment of retinal diseases.

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Arrestins: Introducing Signaling Bias Into Multifunctional Proteins

Cited by 6 publications

References 95 publications

β-arrestin2 regulating β2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression

β-arrestin2 regulating β2-adrenergic receptor signaling in hepatic stellate cells contributes to hepatocellular carcinoma progression

New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation

The Role of Adrenoceptors in the Retina

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