Chapter Three - Ubiquitination and Protein Turnover of G-Protein-Coupled Receptor Kinases in GPCR Signaling and Cellular Regulation

Penela, Petronila

doi:10.1016/bs.pmbts.2016.04.002

Cited by 25 publications

(26 citation statements)

References 145 publications

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“…Changes in FAIM2 ubiquitination and proteasome degradation after detachment was a specific response modulating posttranslational FAIM2 modification, as we did not find a global decrease in protein ubiquitination (Figure 9b) or increase in the levels of GRK, a well-known proteasome substrate in the retina (Figure 9c). 19,20 Similar to in vivo findings, proteasome inhibition resulted in increased FAIM2 ubiquitination in 661 W cells ( Figure 9d) and FAS activation did not affect global ubiquitination of proteins in vitro (Figure 9e). These results demonstrate that FAIM2 levels are regulated by proteasomemediated degradation and JNK-mediated FAIM2 phosphorylation prevents FAIM2 proteasome targeting and leads to FAIM2 accumulation independent of gene transcription.…”

Section: Resultssupporting

confidence: 82%

FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina

et al. 2017

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We report the neuroprotective role of FAS apoptotic inhibitory molecule 2 (FAIM2), an inhibitor of the FAS signaling pathway, during stress-induced photoreceptor apoptosis. Retinal detachment resulted in increased FAIM2 levels in photoreceptors with higher amounts detected at the tips of outer segments. Activation of FAS death receptor via FAS-ligand led to JNK-mediated FAIM2 phosphorylation, decreased proteasome-mediated degradation and increased association with the FAS receptor. Photoreceptor apoptosis was accelerated in Faim2 knockout mice following experimental retinal detachment. We show that FAIM2 is primarily involved in reducing stress-induced photoreceptor cell death but this effect was transient. FAIM2 was found to interact with both p53 and HSP90 following the activation of the FAS death pathway and FAIM2/HSP90 interaction was dependent on the phosphorylation of FAIM2. Lack of FAIM2 led to increased expression of proadeath genes Fas and Ripk1 in the retina under physiologic conditions. These results demonstrate that FAIM2 is an intrinsic neuroprotective factor activated by stress in photoreceptors and delays FAS-mediated photoreceptor apoptosis. Modulation of this pathway to increase FAIM2 expression may be a potential therapeutic option to prevent photoreceptor death.

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Section: Resultssupporting

confidence: 82%

FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina

et al. 2017

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“…3D). Based on such data, posttranscriptional regulation of GRK2 by TNF-␣ was investigated, considering, in particular, the involvement of the proteasome pathway, which has been identified as a major mechanism for modulating GRK2 expression levels (34)(35)(36). For this purpose, MSCs were challenged with the proteasome inhibitor MG-132 (37) in the absence or presence of the inflammatory cytokine for 48 h. As depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

Osteogenesis Is Improved by Low Tumor Necrosis Factor Alpha Concentration through the Modulation of Gs-Coupled Receptor Signals

Daniele

Natali

Giacomelli

et al. 2017

Molecular and Cellular Biology

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In the early phase of bone damage, low concentrations of the cytokine tumor necrosis factor alpha (TNF-α) favor osteoblast differentiation. In contrast, chronic high doses of the same cytokine contribute to bone loss, demonstrating opposite effects depending on its concentration and on the time of exposure. In the bone microenvironment, TNF-α modulates the expression/function of different G protein-coupled receptors (GPCRs) and of their regulatory proteins, GPCR-regulated kinases (GRKs), thus dictating their final biological outcome in controlling bone anabolic processes. Here, the effects of TNF-α were investigated on the expression/responsiveness of the A adenosine receptor (AAR), a Gs-coupled receptor that promotes mesenchymal stem cell (MSC) differentiation into osteoblasts. Low TNF-α concentrations exerted a prodifferentiating effect on MSCs, pushing them toward an osteoblast phenotype. By regulating GRK2 turnover and expression, the cytokine impaired AAR desensitization, accelerating receptor-mediated osteoblast differentiation. These data supported the anabolic effect of TNF-α submaximal concentration and demonstrated that the cytokine regulates GPCR responses by interfering with the receptor desensitization machinery, thereby enhancing the anabolic responses evoked by AAR ligands. Overall, these results indicated that GPCR desensitization plays a pivotal role in osteogenesis and that its manipulation is an effective strategy to favor bone remodeling.

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“…25 β-arrestin-dependent Src activity in turn regulates GRK2 levels, providing a negative feedback on GPCR desensitization. 59 Additionally, β-arrestin-Src complexes phosphorylate and modulate the activity of the endocytic proteins, dynamin I and β2-adaptin and regulate clathrin-dependent internalization of GPCRs including AT 1a R, β 2 AR, V 2 R and bradykinin B2 receptor. 25 β-arrestin-Src kinase association can also facilitate exocytosis and granule release as shown for the interleukin 8 receptor CXCR1.…”

Section: β-Arrestin-dependent Signaling Via Scaffoldingmentioning

confidence: 99%

G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

Jean-Charles¹,

Kaur

Shenoy³

2017

Journal of Cardiovascular Pharmacology

188

106

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β-arrestin1 (or arrestin2) and β-arrestin2 (or arrestin3) are ubiquitously expressed cytosolic adaptor proteins that were originally discovered for their inhibitory role in G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins. However, further biochemical characterization revealed that β-arrestins do not just ‘block’ the activated GPCRs, but trigger endocytosis and kinase activation leading to specific signaling pathways that can be localized on endosomes. The signaling pathways initiated by β-arrestins were also found to be independent of G protein activation by GPCRs. The discovery of ligands that blocked G protein activation but promoted β-arrestin binding, or vice-versa, suggested the exciting possibility of selectively activating intracellular signaling pathways. Additionally, it is becoming increasingly evident that β-arrestin-dependent signaling is extremely diverse and provokes distinct cellular responses through different GPCRs even when the same effector kinase is involved. In this review, we summarize various signaling pathways mediated by β-arrestins and highlight the physiologic effects of β-arrestin-dependent signaling.

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Chapter Three - Ubiquitination and Protein Turnover of G-Protein-Coupled Receptor Kinases in GPCR Signaling and Cellular Regulation

Cited by 25 publications

References 145 publications

FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina

FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina

Osteogenesis Is Improved by Low Tumor Necrosis Factor Alpha Concentration through the Modulation of Gs-Coupled Receptor Signals

G Protein–Coupled Receptor Signaling Through β-Arrestin–Dependent Mechanisms

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