Differential Nucleocytoplasmic Shuttling of β-Arrestins

Scott, Mark G. H.; Rouzic, Erwann Le; Périanin, Axel; Pierotti, Vincenzo; Enslen, Hervé; Bénichou, Serge; Marullo, Stéfano; Benmerah, Alexandre

doi:10.1074/jbc.m207552200

Cited by 194 publications

(106 citation statements)

References 41 publications

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“…Further experiments to examine the involvement of β-arrestin in this pathway and the identification of the relevant PKB targets are required. At this point, it is still unclear if the nuclear localized receptors interact with β-arrestin or GRKs although both are present in the nucleus [36,37]. Pim-1, a protein kinase downstream of PKB, may also be involved as it plays a pivotal role in the inhibition of both apoptosis and hypertrophy in cardiomyocytes, and its expression affects both JNK and ERK pathways [38].…”

Section: Discussionmentioning

confidence: 99%

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Vaniotis

Duca

Trieu

et al. 2011

Cellular Signalling

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Both β 1 -and β 3 -adrenergic receptors (β 1 ARs and β 3 ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the βAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18 S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially * Corresponding authors. Hébert is to be contacted

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Section: Discussionmentioning

confidence: 99%

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Vaniotis

Duca

Trieu

et al. 2011

Cellular Signalling

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“…Arr3 is known to be distributed in the cytoplasm and associated to plasma and endosomal membranes. Arr3 is predominantly found out of the nucleus due to the presence of its two-leucine nuclear export signal (45). However, Neuhaus et al (46) reported Arr3 to be localized in the nucleus of HEK293 cells and mature spermatozoa.…”

Section: Pgds (Data Not Shown) Strong Growth Was Also Observed On Trpmentioning

confidence: 99%

An Interaction between L-prostaglandin D Synthase and Arrestin Increases PGD2 Production

Mathurin

Gallant

Germain

et al. 2011

Journal of Biological Chemistry

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L-type prostaglandin synthase (L-PGDS) produces PGDProstaglandins (PGs) 5 are lipid mediators formed from arachidonic acid through the action of cyclooxygenases (COXs). COXs convert arachidonic acid released from the plasma membrane to an intermediate substrate, PGH 2 , which is metabolized by specific synthases to produce PGs like PGD 2 (1, 2). PGD 2 is involved in various physiological processes such as vasodilatation, bronchoconstriction (3), regulation of pain (4), and sleep (5) but is also implicated in inflammatory responses such as asthma (6) and atherosclerosis (7). PGD 2 was shown to exhibit anti-inflammatory properties as well, as increased levels of PGD 2 are observed during the resolution phase of inflammation (8 -10). Recent work by our group showed that PGD 2 displays anabolic properties in bone (11,12).There are two types of prostaglandin D 2 synthase (PGDS). The hematopoietic PGDS (H-PGDS) is glutathione-requiring (13) and is expressed mainly in mast cells (14), megakaryocytes (15), and T-helper 2 lymphocytes (16). The lipocalintype PGDS (L-PGDS), also called ␤-trace, is glutathione-independent and is expressed abundantly in the central nervous system (17, 18), the heart (19), the retina (20), and the genital organs (21). L-PGDS is also the only enzyme among the members of the lipocalin gene family and binds small lipophilic substances like retinoic acid (22), bilirubin (23), and gangliosides (24).The arrestin family consists of ubiquitously expressed arrestin-2 and -3 (also known as ␤-arrestin-1 and -2) and two retinal arrestins (25). Arrestin-2 and -3 are multifunctional molecules in addition to their well known role in desensitization and internalization of G protein-coupled receptors (26). The identification of numerous non-receptor binding partners has expanded their functions to protein ubiquitination, chemotaxis, apoptosis, mitogen-activated protein kinases activation (27, 28), osteoclastogenesis inhibition (29), and regulation of the interleukin 1 (IL-1) pathway (30).It is remarkable how very little is known about the interaction partners and the mechanisms regulating the activity of PG synthases considering their crucial physiological and pathological roles and the clinical problems associated with the long term use of COX inhibitors. Here we show that arrestin-3 interacts with L-PGDS and increases L-PGDS-mediated PGD 2 production. An arrestin-3 peptide was identified as capable of inducing PGD 2 production by L-PGDS. This is important because it shows that by identifying interacting partners of PG synthases we can not only further our understanding of the

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“…For example, ␤-arr2 (not ␤-arr1) redistributes the prooncogenic ubiquitin ligase Mdm2 (9) and the JNK3 kinase (10) from the nucleus to the cytoplasm. This property depends on the presence of a leucine-rich nuclear export signal in the C terminus of ␤-arr2, which mediates the nuclear export of ␤-arr2 by leptomycin B-sensitive exportins (11). More recently, it has been reported that, despite the fact that ␤-arr1 does not shuttle between the nucleus and the cytoplasm like ␤-arr2, it can accumulate in the nucleus in response to receptor activation and interact with specific promoters.…”

mentioning

confidence: 99%

“…In particular, delocalization of nuclear proteins, such as Mdm2, via the permanent nucleocytoplasmic shuttling of ␤-arr2, may occur even in the absence of receptor activation (9,11) and might thus involve ␤-arr2 oligomers. This hypothesis was investigated here.…”

mentioning

confidence: 99%

β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53

Boularan

Scott

Bourougaa

et al. 2007

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

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␤-arrestins (␤-arrs), two ubiquitous proteins involved in serpentine heptahelical receptor regulation and signaling, form constitutive homo-and heterooligomers stabilized by inositol 1,2,3,4,5,6-hexakisphosphate (IP6). Monomeric ␤-arrs are believed to interact with receptors after agonist activation, and therefore, ␤-arr oligomers have been proposed to represent a resting biologically inactive state. In contrast to this, we report here that the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require ␤-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of ␤-arr2. Mutation of the IP6-binding sites impair oligomerization, reduce interaction with Mdm2, and inhibit p53-dependent antiproliferative effects of ␤-arr2, whereas the competence for receptor regulation and signaling is maintained. These observations suggest that the intracellular concentration of ␤-arr2 oligomers might control cell survival and proliferation. bioluminescence resonance energy transfer ͉ FRET ͉ nucleocytoplasmic shuttling ͉ ubiquitination

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Differential Nucleocytoplasmic Shuttling of β-Arrestins

Cited by 194 publications

References 41 publications

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

An Interaction between L-prostaglandin D Synthase and Arrestin Increases PGD2 Production

β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53

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