Beta-arrestins: Traffic cops of cell signaling

Howard Hughes Medical Institute, Duke University Medical Center, DUMC Box 3821, Durham, NC 27710, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 05/2004; 16(2):162-8. DOI: 10.1016/
Source: PubMed


Once thought to function only in the desensitization of seven membrane spanning receptors (7MSRs), the ubiquitous beta-arrestin molecules are increasingly appreciated to play important roles in the endocytosis and signaling of these receptors. These functions reflect the ability of the beta-arrestins to bind an ever-growing list of signaling and endocytic elements, often in an agonist-dependent fashion. One heavily studied system is that leading to MAP kinase activation via beta-arrestin-mediated scaffolding of these pathways in a receptor-dependent fashion. The beta-arrestins are also found to be involved in the regulation of novel receptor systems, such as Frizzled and TGFbeta receptors.

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    • "Role of b-Arrestin 2 in GRK2-Mediated Endothelial Derangement. It is well established that b-arrestins, whose recruitment is mediated by GRKs, can act as scaffold molecules that bring different signaling molecules into a receptor complex (Lefkowitz and Whalen, 2004; DeWire et al., 2007; Premont and Gainetdinov, 2007). Our Western blotting analysis showed that HUVECs constitutively expressed b-arrestin 2 (see Figs. 5B and 6). "
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    ABSTRACT: G protein-coupled receptor kinase 2 (GRK2) participates together with β-arrestins in the regulation of G protein-coupled receptor signaling, but emerging evidence suggests that GRK2 can interact with a growing number of proteins involved in signaling mediated by other membrane receptor families under various pathologic conditions. We tested the hypothesis that GRK2 may be an important contributor to vascular endothelial dysfunction in diabetes. Human umbilical venous endothelial cells (HUVECs) were exposed to high glucose and high insulin (HG/HI) in order to mimic insulin-resistant diabetic conditions. GRK2 expression and membrane translocation were up-regulated under HG/HI conditions. HG/HI did not modify activation of Akt and endothelial nitric oxide synthase (eNOS), but GRK2 inhibitor or small interfering RNA (siRNA) resulted in an increase in Akt and eNOS activation in HUVECs exposed to HG/HI. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation was increased after exposure to HG/HI, which was prevented by GRK2 inhibitor or siRNA. ERK1/2-mediated GRK2 phosphorylation at Ser-670 confirmed that ERK1/2 participated in a negative feedback regulatory loop. In HEK293T cells which overexpressed GRK2, Akt activity was unchanged, while ERK1/2 activity was raised. The effect of GRK inhibitor treatment on Akt/eNOS signaling was associated with membrane translocation of β-arrestin 2. The experiments with β-arrestin 2 siRNA showed that β-arrestin 2 may act as a positive modulator of Akt/eNOS signaling. Our studies reveal that GRK2, which is up-regulated by HG/HI, leads to a tonic inhibition of the insulin Akt/eNOS pathway in endothelial cells. We provide new insights into the pathogenesis of diabetes-associated vascular endothelial dysfunction.
    Preview · Article · Feb 2014 · Journal of Pharmacology and Experimental Therapeutics
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    • "In the fi rst 5 min of spontaneous activity in the open fi eld arena, fl ies show intensive exploration of a novel environment , with crucial role of Kurtz nonvisual arrestin in the nervous system (Liu et al. 2007). Th e krz gene encodes the only nonvisual arrestin in Drosophila (Roman et al. 2000) which is important scaff olding proteins regulating the activity of several families of cell-surface receptors (Lefkowitz and Whalen 2004). In later phase of fl ies ' activity in the open fi eld arena dopamine takes place (Bainton et al. 2000, Friggi-Grelin et al. 2003). "
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    • "However, β-arrestins are also essential for endocytosis of receptors via clathrin-coated pits through interactions with clathrin [22] and AP-2 adaptor protein [23]. More recently, it has been shown that β-arrestins coordinate several G protein-independent GPCR signaling cascades [24]–[26]. In these cases, the β-arrestin typically serves as a molecular scaffold, assembling multiple elements of a signaling cascade at activated receptors, thereby regulating the temporal and spatial activity of the pathway. "
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