β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

Piu, Fabrice; Gauthier, Natalie K; Wang, F

doi:10.1038/sj.onc.1209024

Cited by 17 publications

(12 citation statements)

References 48 publications

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“…This is not the first example of cell growth modulation via ␤-arr2. Indeed, it was reported recently that ␤-arr2 stimulates the transcriptional activation of retinoid RAR receptors and that the inhibition of PC12 cell growth in response to nerve growth factor involves the ␤-arr2-and ERK2-dependent transcriptional activation of the RAR-␤2 receptor (33). Together with our data, these observations suggest a possible previously unappreciated role of ␤-arrs in the control of cell division with multiple points of impact.…”

Section: Discussionsupporting

confidence: 78%

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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Section: Discussionsupporting

confidence: 78%

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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“…As the turnover of retinoid receptors is regulated by their phosphorylation status, it is plausible that in this study, decreased expression of these receptors might be due to their aberrant phosphorylation status by MAPKs. A recent report by Piu et al (30) shows that RARh2 is phosphorylated by extracellular signal-regulated kinase 2; second, in various cancers including melanoma loss of RARh, expression has been correlated to the hypermethylated status of RARh promoter (31) and/or to a deficient acetylation of histones (32), which in both cases result in repressed chromatin. Apparently, the presence of an epigenetically silent RARh2 promoter correlates with the lack of RARa and causes resistance to the growthinhibitory effect of retinoic acid.…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of Retinoid Receptors in Melanoma: Entailment in Tumorigenesis and Prognosis

Chakravarti¹,

Lotan²,

Diwan³

et al. 2007

Clinical Cancer Research

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Purpose: Retinoids inhibit proliferation and induce differentiation in melanoma cells. Retinoic acid receptors (RAR) and retinoid X receptors (RXR) mediate the various modulatory effects of retinoids in cells. We have studied the in situ expression of each RAR and RXR protein (a, h, g) in a large series of melanocytic lesions and correlated the expression with clinicopathologic features and prognosis of the patients. Experimental Design:Tissue microarray blocks of 226 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic and nuclear expression of RAR and RXR protein (a, h, g).Results: A significant decrease of RARh protein (P < 0.0001), nuclear expression of RARg (P < 0.0001), and RXRa (P < 0.0001) was found in primary and metastatic melanomas as compared with nevi. Loss of nuclear immunoreactivity for RARg (P = 0.048) and RXRa (P = 0.001) was observed in the lesions showing vertical growth pattern. In addition, in patients with concomitant loss of cytoplasmic staining for RARa and RXRa, the probability of overall survival (log-rank test, P = 0.002) and disease-specific survival (log-rank test, P = 0.014) was significantly lower. Conclusions: Aberrant expression of retinoid receptors seems to be a frequent event in melanoma and suggests an impairment of the retinoid pathway in this cancer. Our data indicate the loss of retinoid receptor expression with melanoma progression and suggest a possible prognostic significance of the analysis of retinoid receptors in melanoma.

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“…Piu and colleagues have demonstrated that ␤-arrestin 2 enhances the transcriptional activity of the nuclear receptor RAR-␤2 and this effect is dependent upon the recruitment of ERK2 and its direct interaction with RAR-␤2 in the cytoplasm (Piu et al, 2006). ␤-arrestin-2-dependent p38 activation provides another example.…”

Section: Regulation Of Subcellular Compartmentalization Of Mapksmentioning

confidence: 99%

β-arrestin signaling and regulation of transcription

Pei

2007

Journal of Cell Science

228

200

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β-arrestin 1 and β-arrestin 2 are well-known negative regulators of G-protein-coupled receptor (GPCR) signaling. Upon GPCR activation, β-arrestins translocate to the cell membrane and bind to the agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, thus causing desensitization. However, accumulating evidence indicates that β-arrestins also function as scaffold proteins that interact with several cytoplasmic proteins and link GPCRs to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that, in response to activation of certain GPCRs, β-arrestins translocate from the cytoplasm to the nucleus and associate with transcription cofactors such as p300 and cAMP-response element-binding protein (CREB) at the promoters of target genes to promote transcription. They also interact with regulators of transcription factors, such as IκBα and MDM2, in the cytoplasm and regulate transcription indirectly. This β-arrestin-mediated regulation of transcription appears to play important roles in cell growth, apoptosis and modulation of immune functions.

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β-arrestin 2 modulates the activity of nuclear receptor RAR β2 through activation of ERK2 kinase

Cited by 17 publications

References 48 publications

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

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

Decreased Expression of Retinoid Receptors in Melanoma: Entailment in Tumorigenesis and Prognosis

β-arrestin signaling and regulation of transcription

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