Interaction with receptor for activated C-kinase 1 (RACK1) sensitizes the phosphodiesterase PDE4D5 towards hydrolysis of cAMP and activation by protein kinase C

Bird, Rebecca J.; Baillie, George S.; Yarwood, Stephen J.

doi:10.1042/bj20101010

Cited by 33 publications

(24 citation statements)

References 35 publications

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“…RACK1 presumably recruits these proteins to their appropriate subcellular sites, thereby integrating their actions into intracellular signaling pathways (14). Accordingly, RACK1 has recently been shown to enable cross-talk between the PKC and cAMP signaling pathways by mediating the PKCdependent activation of PDE 4 D 5 in response to elevated intracellular cAMP levels (16).…”

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confidence: 99%

RACK1/Asc1p, a Ribosomal Node in Cellular Signaling

Rachfall

Schmitt

Bandau

et al. 2013

Molecular & Cellular Proteomics

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§ RACK1/Asc1p and its essential orthologues in higher eukaryotes, such as RACK1 in metazoa, are involved in several distinct cellular signaling processes. The implications of a total deletion have never been assessed in a comprehensive manner. This study reveals the major cellular processes affected in a Saccharomyces cerevisiae ⌬asc1 deletion background via de novo proteome and transcriptome analysis, as well as subsequent phenotypical characterizations. The deletion of ASC1 reduces iron uptake and causes nitrosative stress, both known indicators for hypoxia, which manifests in a shift of energy metabolism from respiration to fermentation in the ⌬asc1 strain. Asc1p further impacts cellular metabolism through its regulative role in the MAP kinase signal transduction pathways of invasive/filamentous growth and cell wall integrity. In the ⌬asc1 mutant strain, aberrations from the expected cellular response, mediated by these pathways, can be observed and are linked to changes in protein abundances of pathway-targeted transcription factors. Evidence of the translational regulation of such transcription factors suggests that ribosomal Asc1p is involved in signal transduction pathways and controls the biosynthesis of the respective final transcriptional regulators. Molecular & Cellular

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confidence: 99%

RACK1/Asc1p, a Ribosomal Node in Cellular Signaling

Rachfall

Schmitt

Bandau

et al. 2013

Molecular & Cellular Proteomics

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“…These phenomena raised an interesting question on the mechanisms of P-gp-mediated activation of Erk1/2 signaling. Rack1 regulated P-gp activity, and Rack1 was implicated in the activation of Erk1/2 signaling [57,58]. We inferred that Rack1 may be involved in P-gp-mediated activation of Erk1/2.…”

Section: Discussionmentioning

confidence: 94%

Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells

Yang

Wang

et al. 2016

IJMS

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The emergence of multidrug resistance is always associated with more rapid tumor recurrence and metastasis. P-glycoprotein (P-gp), which is a well-known multidrug-efflux transporter, confers enhanced invasion ability in drug-resistant cells. Previous studies have shown that P-gp probably exerts its tumor-promoting function via protein-protein interaction. These interactions were implicated in the activation of intracellular signal transduction. We previously showed that P-gp binds to Anxa2 and promotes the invasiveness of multidrug-resistant (MDR) breast cancer cells through regulation of Anxa2 phosphorylation. However, the accurate mechanism remains unclear. In the present study, a co-immunoprecipitation coupled with liquid chromatography tandem mass spectrometry-based interactomic approach was performed to screen P-gp binding proteins. We identified Rack1 as a novel P-gp binding protein. Knockdown of Rack1 significantly inhibited proliferation and invasion of MDR cancer cells. Mechanistic studies demonstrated that Rack1 functioned as a scaffold protein that mediated the binding of P-gp to Anxa2 and Src. We showed that Rack1 regulated P-gp activity, which was necessary for adriamycin-induced P-gp-mediated phosphorylation of Anxa2 and Erk1/2. Overall, the findings in this study augment novel insights to the understanding of the mechanism employed by P-gp for promoting migration and invasion of MDR cancer cells.

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“…Also in these systems, PDE4D5 has been shown to play a pivotal role in the switching of signalling between b2-adrenoceptor-mediated cAMP production via Gs proteins and activation of the ERK pathway via Gi-mediated b-arrestin activity Bolger et al, 2003;. Unlike any other PDE isoform, PDE4D5 is able to bind to the scaffold protein Receptors for Activated C Kinase (RACK)1, and this observation has led to the recent description of crosstalk between the cAMP and PKC signalling pathways (Bird et al, 2010). It is clear from these studies that the ability of PDE4D5 to tightly orchestrate such key cellular endpoints as relaxation and proliferation via cAMP/ERK would make it exceptionally important in airway function.…”

Section: Control Of Camp Degradationmentioning

confidence: 99%

Novel cAMP signalling paradigms: therapeutic implications for airway disease

Billington

Hall

2012

British J Pharmacology

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Since its discovery over 50 years ago, cAMP has been the archetypal second messenger introducing students to the concept of cell signalling at the simplest level. As explored in this review, however, there are many more facets to cAMP signalling than the path from Gs-coupled receptor to adenylyl cyclase (AC) to cAMP to PKA to biological effect. After a brief description of this canonical cAMP signalling pathway, a snapshot is provided of the novel paradigms of cAMP signalling. As in the airway the cAMP pathway relays the major bronchorelaxant signal and as such is the target for frontline therapy for asthma and COPD, particular emphasis is given to airway disease and therapy. Areas discussed include biased agonism, continued signalling following internalization, modulation of cAMP by AC, control of cAMP degradation, cAMP and calcium crosstalk, Epac-mediated signalling and finally the implications of altered genotypes will be considered. LINKED ARTICLESThis article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2 Abbreviations AC, adenylyl cyclase; ASM, airway smooth muscle; CFP, cyan fluorescent protein; COPD, chronic obstructive pulmonary disease; CREB, cAMP response element binding; Epac, exchange protein directly activated by cAMP; GEF, guanine nucleotide exchange factor; GRK, G-protein coupled receptor kinase; hASM, human airway smooth muscle; IP3, inositol trisphosphate; RACK1, receptors for activated C kinase 1; SERCA, sarco/endoplasmic reticulum Ca 2+ -ATPase; SOCC, store-operated calcium channel; TSH, thyroid-stimulating hormone; YFP, yellow fluorescent protein cAMP is the classical second messenger discovered by Earl W Sutherland Jr. and Theodore W Rall in 1956 (Sutherland andRall, 1958). To date, research into cAMP has led to five Nobel awards (Beavo and Brunton, 2002) and is the subject of almost 100 000 publications on PubMed. In the last decade, in particular, the generation and enhanced use of fluorescent probes allowing quantification/visualisation of cAMP signalling at a pharmacological, spatial and temporal level has added significantly to our understanding of this pathway (Lohse et al., 2008;Hill et al., 2010).In the airways, cAMP is a critical regulator of airway tone being the major pro-relaxant effector in airway smooth muscle (ASM) bundles. As such, it is a key therapeutic target in airway disease being the transducer of the signal induced by clinically used b2-adrenoceptor agonists (e.g. indacaterol, formoterol, salmeterol) which results in bronchodilation and symptomatic relief. Although outside the scope of this review, it should be mentioned that in addition to its pro-relaxant role in ASM, cAMP modulates a range of diverse cellular events pertinent to airway function including the production and secretion of inflammatory mediators and extracellular matrix, proliferation, migration and in epithelial cells mucus secretion, wound healing, anion transport and ciliary beating (Sal...

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Interaction with receptor for activated C-kinase 1 (RACK1) sensitizes the phosphodiesterase PDE4D5 towards hydrolysis of cAMP and activation by protein kinase C

Cited by 33 publications

References 35 publications

RACK1/Asc1p, a Ribosomal Node in Cellular Signaling

RACK1/Asc1p, a Ribosomal Node in Cellular Signaling

Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells

Novel cAMP signalling paradigms: therapeutic implications for airway disease

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