Insulin-Like Growth Factor I Controls a Mutually Exclusive Association of RACK1 with Protein Phosphatase 2A and β1 Integrin To Promote Cell Migration

Kiely, Patrick A.; O׳Gorman, Denise M.; Luong, Ken; Ron, Dorit; O’Connor, Rosemary

doi:10.1128/mcb.01868-05

Cited by 97 publications

(114 citation statements)

References 42 publications

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“…Here we showed that RACK1 recruited both PP2A and Akt in response to ephrin-B1-Fc-induced activation of EphB3, facilitating the phosphatase/substrate interaction by serving as a scaffold, and consequently abrogated Akt activity. Previous observations have shown that PP2A can interact with RACK1 in some circumstances [39][40][41] . For example, insulin-like growth factor 1 (IGF-1) controls the mutually exclusive association of RACK1 with PP2A and β1 integrin.…”

Section: Discussionmentioning

confidence: 99%

EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex

Gao

et al. 2012

Nat Commun

108

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Eph receptors are implicated in regulating the malignant progression of cancer. Here we find that despite overexpression of EphB3 in human non-small-cell lung cancer, as reported previously, the expression of its cognate ligands, either ephrin-B1 or ephrin-B2, is significantly downregulated, leading to reduced tyrosine phosphorylation of EphB3. Forced activation of EphB3 kinase in EphB3-overexpressing non-small-cell lung cancer cells inhibits cell migratory capability in vitro as well as metastatic seeding in vivo. Furthermore, we identify a novel EphB3-binding protein, the receptor for activated C-kinase 1, which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A, Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. our study reveals a novel tumour-suppressive signalling pathway associated with kinase-activated EphB3 in non-small-cell lung cancer, and provides a potential therapeutic strategy by activating EphB3 signalling, thus inhibiting tumour metastasis.

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Section: Discussionmentioning

confidence: 99%

EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex

Gao

et al. 2012

Nat Commun

108

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“…S1), were used for vector-based small hairpin RNA expression. The two sequences are: siRACK1-a (20 nt, GAC CAT CAT CAT GTG GAA GC), which was designed to target rat and human RACK1 mRNA using the online siRNA Retriever (available from Cold Spring Harbor Laboratories), and siRACK1-b (19 nt, CCA TCA AGC TAT GGA ATA C), which targets the human gene (12). For cloning of each of the siRACK1s, two complementary oligonucleotides were synthesized as follows: 5Ј-GATCCC (20 nt, sense) TTGAT-ATCCG (20 nt, antisense) TTTTTT CCAAA-3Ј and 3Ј-GG (20 nt antisense) AACTATAGGC (20 nt, sense) AAAAAA GGTTTTCGA-5Ј flanked by BamHI and HindIII residues.…”

Section: Methodsmentioning

confidence: 99%

“…These interactions, and others, put RACK1 at a focal point for spatial and temporal regulation of various signaling cascades. For example, in transformed cultured cancer cells, RACK1 was shown to form a scaffolding complex that includes the IGF-1R, ␤1 integrin, and focal adhesion kinase (6,9,10,12). In addition, RACK1 is also found at the 40 S ribosomal subunit (3,13,14) and was shown to bridge protein kinase C-mediated signaling to the ribosomal translation machinery (15).…”

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confidence: 99%

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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Scaffolding proteins are major contributors to the spatial and temporal orchestration of signaling cascades and hence cellular functions. RACK1 is a scaffolding protein that plays an important role in the regulation of, and cross-talk between, various signaling pathways. Here we report that RACK1 is a mediator of chromatin remodeling, resulting in an exon-specific expression of the brain-derived neurotrophic factor (BDNF) gene. Specifically, we found that following the activation of the cAMP pathway, nuclear RACK1 localizes at the promoter IV region of the BDNF gene by its association with histones H3 and H4, leading to the dissociation of the transcription repressor methyl-CpGbinding protein 2 (MeCP2) from the promoter, resulting in the acetylation of histone H4. These chromatin modifications lead to the activation of the promoter and to the subsequent promoter-controlled transcription of BDNF exon IV. Our findings expand our knowledge regarding the function of scaffolding proteins such as RACK1. Furthermore, this novel mechanism for the regulation of exon-specific expression of the BDNF gene by RACK1 could have implications on the neuronal functions of the growth factor including synaptic plasticity, learning, and memory.Signal transduction cascades are tightly regulated events. Scaffolding proteins play an essential role in the spatial and temporal regulation of individual enzymes and provide the link between extracellular events and intracellular compartments including the nucleus (1). Scaffolding proteins, by means of protein-protein interactions, provide platforms for protein assembly. The scaffolding protein RACK1, which was originally identified as an anchoring protein of protein kinase C ␤II (2), belongs to the WD40 family of proteins characterized by seven WD40 repeats forming a seven-blade ␤-propeller structure (3, 4). This particular structure allows RACK1 to interact with various enzymes including Fyn kinase (5), focal adhesion kinase (6), receptor protein tyrosine phosphatase (7), the cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4D5 (8), as well as the intracellular tails of receptors such as the insulin-like growth factor 1 receptor (IGF-1R) (9, 10), the inositol 1,4,5-triphosphate receptor (11), and ion channels such as the NR2B subunit of the N-methyl D-aspartate receptors (5). These interactions, and others, put RACK1 at a focal point for spatial and temporal regulation of various signaling cascades. For example, in transformed cultured cancer cells, RACK1 was shown to form a scaffolding complex that includes the IGF-1R, ␤1 integrin, and focal adhesion kinase (6,9,10,12). In addition, RACK1 is also found at the 40 S ribosomal subunit (3,13,14) and was shown to bridge protein kinase C-mediated signaling to the ribosomal translation machinery (15). RACK1 plays an important role in the central nervous system (16). For example, RACK1 links Fyn kinase to its substrate, the NR2B subunit of the N-methyl D-aspartate receptor (5, 17), and contributes to the regulation of channel activity (18)...

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“…We have previously established that PP2A competes with β1 integrin for binding to WD7 of RACK1 and that the binding was regulated by IGF-I and required for IGF-I-mediated cell adhesion [30,31]. We set out to further characterise the interaction between RACK1 and the PP2A holoenzyme.…”

Section: Mapping the Interaction Between Rack1 And The Pp2a-c Subunitmentioning

confidence: 99%

“…PP2A directly interacts with RACK1 in an IGF-1 dependent manner where RACK1 serves to stabilise PP2A activity [30,31]. A reduction in RACK1 expression decreases the phosphatase activity of PP2A, which has been shown to promote cell migration in cancer cells [31].…”

Section: Introductionmentioning

confidence: 99%

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Kiely

Adams

Hayes

et al. 2017

Cellular Signalling

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. (2017) RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells. Cellular Signalling, 35, pp. 290-300. (doi:10.1016Signalling, 35, pp. 290-300. (doi:10. /j.cellsig.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/128660/ RACK1/PP2A complex is required for cell adhesion, proliferation, migration, invasion.Potential role for the RACK1/PP2A complex in the progression of breast cancer. KeywordsBreast Cancer, RACK1, PP2A, Protein-Protein Interactions. ABSTRACTConflicting reports implicate the scaffolding protein RACK1 in the progression of breast cancer. RACK1 has been identified as a key regulator downstream of growth factor and adhesion signalling and as a direct binding partner of PP2A. Our objective was to further characterise the interaction between PP2A and RACK1 and to advance our understanding of this complex in breast cancer cells. We examined how the PP2A holoenzyme is assembled on the RACK1 scaffold in MCF-7 cells. We used immobilized peptide arrays representing the entire PP2A-catalytic subunit to identify candidate amino acids on the C subunit of PP2A that might be involved in binding of RACK1. We identified the RACK1 interaction sites on PP2A. Stable cell lines expressing PP2A with FR69/70AA, R214A and Y218F substitutions were generated and it was confirmed that the RACK1/PP2A interaction is essential to stabilize PP2A activity. We used Real-Time Cell Analysis and a series of assays to demonstrate that disruption of the RACK1/PP2A complex also reduces the adhesion, proliferation, migration and invasion of breast cancer cells and plays a role in maintenance of the cancer phenotype. This work has significantly advanced our understanding of the RACK1/PP2A complex and suggests a pro-carcinogenic role for the RACK1/PP2A interaction. This work suggests that approaches to target the RACK1/PP2A complex are a viable option to regulate PP2A activity and identifies a novel potential therapeutic target in the treatment of breast cancer.

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Insulin-Like Growth Factor I Controls a Mutually Exclusive Association of RACK1 with Protein Phosphatase 2A and β1 Integrin To Promote Cell Migration

Cited by 97 publications

References 42 publications

EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex

EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

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