cAMP-dependent Protein Kinase Regulates Ubiquitin-Proteasome-mediated Degradation and Subcellular Localization of the Nuclear Receptor Coactivator GRIP1

Hoang, Tuyen; Fenne, Ingvild S.; Cook, Carol A.; Børud, Bente; Bakke, Marit; Lien, Ernst A.; Mellgren, Gunnar

doi:10.1074/jbc.m409746200

Cited by 68 publications

(50 citation statements)

References 67 publications

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“…Interestingly, although prolonged treatment with cAMP leads to the proteasome-dependent degradation of GRIP1 (Hoang et al 2004), early during induction, cAMP stimulates the recruitment of GRIP1 to the ERa target gene pS2 (Fenne et al 2008). Although it was not determined whether this is necessary for cAMP activation of ERa, it is intriguing to speculate that, in this case, the recruitment of GRIP1 to ERa may be CARM1-dependent, rather than the other way around, as in the presence of E2 (Fig.…”

Section: Carm1 Is the Link Between Pka And Eramentioning

confidence: 95%

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

Carascossa

Dudek²,

Cenni³

et al. 2010

Genes Dev.

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The estrogen receptor a (ERa) is activated as a transcription factor by both estrogen and a large variety of other extracellular signals. The mechanisms of this ligand-independent activation, notably by cAMP signaling, are still largely unknown. We now close the gap in the signaling pathway between cAMP and ERa. Whereas the direct phosphorylation of ERa by the cAMP-activated protein kinase A (PKA) is dispensable, the phosphorylation of the coactivator-associated arginine methyltransferase 1 (CARM1) by PKA at a single serine is necessary and sufficient for direct binding to the unliganded hormone-binding domain (HBD) of ERa, and the interaction is necessary for cAMP activation of ERa. Sustained PKA activity promoting a constitutive interaction may contribute to tamoxifen resistance of breast tumors. Binding and activation involve a novel regulatory groove of the ERa HBD. As a result, depending on the activating signal, ERa recruits different coactivator complexes to regulate alternate sets of target genes.[Keywords: Steroid receptor; signaling; coactivator; protein kinase A; breast cancer; endocrine resistance] Supplemental material is available at http://www.genesdev.org.

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Section: Carm1 Is the Link Between Pka And Eramentioning

confidence: 95%

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

Carascossa

Dudek²,

Cenni³

et al. 2010

Genes Dev.

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“…Phosphorylation by PKA potentiates retinoic acid receptor a activity by means of increasing interaction with and phosphorylation by cyclin H/cyclin-dependent kinase 7 (32). PKA phosphorylation regulates degradation and subcellular localization of the NR coactivator GRIP1 (33). Our results suggest that PELP1 is another novel substrate of PKA.…”

Section: Discussionmentioning

confidence: 64%

Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway

Nagpal

Nair

Chakravarty

et al. 2008

Molecular Cancer Research

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PELP1 (proline-rich, glutamic acid -rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate -specific antibody. Accordingly, growth factor -mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor -induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling. (Mol Cancer Res 2008;6(5):851 -61)

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“…Forskolin directly activates adenylyl cyclases, whereas IBMX inhibits all of the phosphodiesterases that can degrade cAMP. The combination of these two reagents has been used routinely to achieve sustained intracellular cAMP signaling (31,32).…”

Section: Resultsmentioning

confidence: 99%

Stage-specific Effects of cAMP Signaling during Distal Lung Epithelial Development

Tian

Grumelli

et al. 2006

Journal of Biological Chemistry

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cAMP signaling is postulated to play a role in distal lung epithelial differentiation based on several observations. First, it enhances fibroblast growth factor-induced transdifferentiation of early tracheal epithelium into respiratory epithelium. Second, there are cAMP-responsive elements in the heterologous promoters of Sftpb and Sftpa genes. Third, cAMP augments the effect of dexamethasone in maintaining differentiation of human fetal type II pneumocyte culture. However, this concept has not been thoroughly tested in vivo. In the current study, we modulated cAMP signaling in developing distal lung epithelium in vivo using an inducible transgenic system that expressed a mutant form of G␣ s (G␣ s Q227L). We failed to demonstrate the ability of cAMP to promote distal epithelial maturation during embryonic stages. The results argue against its physiological role in this process. In addition, induction of cAMP signaling at the late pseudoglandular stage but not during the canalicular or saccular stage surprisingly delayed distal differentiation by suppressing the expression of Sftpc, Sftpa, and Aquaporin5 as well as the formation of lamellar bodies. This stage-specific inhibitory effect was observed in the absence of cellular toxicity or changes in branching. Transgenic lungs did not show significant changes in the known pathways that are important for distal differentiation. Therefore, we propose the existence of yet-to-be identified cAMP-sensitive novel regulators of early distal lung epithelial differentiation. Although the delay of differentiation seemed to be reversible at later stages, it still led to pronounced permanent postnatal airspace enlargement due to impaired paracrine function of distal epithelium in regulating alveolar myofibroblast development.Development of the murine lung is initiated at embryonic day 9.5 (E9.5), 2 followed by the pseudoglandular (E10.5-16.5), canalicular (E16.5-17.5), saccular (E17.5-P5), and alveolar stages (P5-35) (1). Three morphogenic events at the pseudoglandular stage are important for distal lung epithelial development. First, through branching morphogenesis, the lung primordium evolves into an extensive network of tubular epithelium composed of eight generations of branches. This process requires a complex interaction between several signaling molecules, such as FGF10 (fibroblast growth factor 10), SHH (sonic hedgehog), and BMP4 (bone morphogenetic protein 4) (2-6). Second, distal-proximal polarity of the branching epithelial tree is established at the same time that branching takes place. As early as E10.5-11.5, the expression of many genes is spatially restricted to the distal end of the branches. Shh, Wnt7b, Id2, thrombospondin, transforming growth factor-␤2, Etv5/Pea3, and Bmp4 are among the genes showing this pattern of expression (7). Distal fate specification requires the BMP4, FGFs, and ␤-catenin pathways. Mice deficient in either the BMP4 or ␤-catenin pathways showed complete transformation of distal epithelium into proximal epithelium with little sign of type...

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cAMP-dependent Protein Kinase Regulates Ubiquitin-Proteasome-mediated Degradation and Subcellular Localization of the Nuclear Receptor Coactivator GRIP1

Cited by 68 publications

References 67 publications

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor α by cAMP

Growth Factor Regulation of Estrogen Receptor Coregulator PELP1 Functions via Protein Kinase A Pathway

Stage-specific Effects of cAMP Signaling during Distal Lung Epithelial Development

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