Protein Kinases and Phosphatases in the Control of Cell Fate

Bononi, Angela; Agnoletto, Chiara; Marchi, Elena De; Marchi, Saverio; Patergnani, Simone; Bonora, Massimo; Giorgi, Carlotta; Missiroli, Sonia; Poletti, Federica; Rimessi, Alessandro; Pinton, Paolo

doi:10.4061/2011/329098

Cited by 249 publications

(237 citation statements)

References 272 publications

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“…In a typical cell, the functions of nearly one-third of proteins are regulated via phosphorylation, and this process controls various biological functions, including cell division, growth, proliferation, and apoptosis (29,30). Depending upon the physiological requirements of the cell, proteins transiently shift from a phosphorylated to a dephosphorylated state, with the balance controlled by protein kinases and phosphatases (30,31).…”

Section: Discussionmentioning

confidence: 99%

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

et al. 2017

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Abstract. Aromatase inhibitors (AIs) are effective endocrine therapeutics for postmenopausal women with estrogen receptor (ER)α-positive breast cancer. However, the efficacy of the treatment is often limited by the onset of AI resistance, owing to the phosphorylation of ERα serine 167 (Ser167). Previous studies have indicated that hyperactivation of the phosphoinositide-3 kinase/RAC serine/threonine-protein kinase signaling pathway occurs in AI-resistant breast cancer models, which coincides with elevated levels of ERα phosphorylation at Ser167. The tumor suppressor serine/threonine-protein phosphatase 2A (PP2A) regulates the phosphatidylinositol 3-kinase/RAC serine/threonine-protein kinase signaling pathway. A previous study indicated that PP2A inhibition decreased ERα Ser167 phosphorylation and estradiol (E 2 )-independent cell growth. The present study investigated the potential relevance of PP2A in E 2 deprivation-resistant MCF-7 cells. E 2 depletion reduced the susceptibility of MCF-7 cells to inhibitors of mechanistic target of rapamycin (mTOR) and significantly increased ERα Ser167 phosphorylation and decreased expression of PP2A. Conversely, long-term E 2 -deprived (LTED) MCF-7 cells, a model of AI-resistant breast cancer, exhibited decreased ERα Ser167 phosphorylation and further upregulation of PP2A in E 2 -containing medium. The PP2A activator forskolin (FSK) significantly inhibited LTED cell proliferation by increasing the effect of everolimus (Eve), an mTOR inhibitor. In summary, the present study provides further evidence that PP2A represents a therapeutic target for AI-resistant breast cancer.

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Section: Discussionmentioning

confidence: 99%

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

et al. 2017

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“…Активация PI3K/Akt-сигнального пути часто ассоциирована с развитием опухолевого ро-ста и резистентностью к противоопухолевой терапии [14]. Важным негативным регулято-ром активности этого пути является PTEN, фосфатаза двойной специфичности, которая удаляет фосфаты с белковых и липидных суб-стратов и ингибирует киназный сигнальный каскад по PI3K/Akt-пути, подавляя активность клеточной пролиферации и индуцируя апоп-тоз [14]. Соматические мутации PTEN, сопро-вождающиеся снижением его активности, были идентифицированы практически во всех типах человеческих опухолей, особенно опухолях мозга, простаты и эндометрия [15].…”

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“…МАРК пред-ставляют собой серин/треонин-специфические киназы, которые регулируют многие функции клеток, включая пролиферацию, жизнеспособ-ность и апоптоз. К МАР-киназам относятся различные подсемейства киназ, такие как ERK (внеклеточные регулируемые сигналом кина-зы), JNK (c-Jun N-терминальные киназы) и р38 MAPK [14]. Показано, что в ходе проведения сигнала по МАРК-пути происходит фосфори-лирование МеК-протеинов, которые фосфо-рилируют и активируют ERK [14].…”

unclassified

“…К МАР-киназам относятся различные подсемейства киназ, такие как ERK (внеклеточные регулируемые сигналом кина-зы), JNK (c-Jun N-терминальные киназы) и р38 MAPK [14]. Показано, что в ходе проведения сигнала по МАРК-пути происходит фосфори-лирование МеК-протеинов, которые фосфо-рилируют и активируют ERK [14]. ERK, в свою очередь, активирует различные протеины из семейства АР-1 транскрипционных факторов, такие как c-fos и с-Jun, что ведет к измене-нию транскрипции различных генов-мишеней в ядре клетки [16].…”

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Molecular mechanisms of regulation of uterine leiomyoma growth

et al. 2017

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Background: to elucidate the molecular mechanisms, regulating growth and proliferation of leiomyoma cells, the estimation of the activity of PR-A and PR-B isoforms of progesterone receptor and PI3K/Akt and MAPК kinases, participating in signal transduction from sex steroids and growth factors, has the special interest. Aim of the work: to investigate the character of the expression of mRNAs of PR-A and PR-B isoforms of progesterone receptor in leiomyomas of different size and different intensity of cellular proliferation, and to elucidate the relationship between the PR-A and PR-B synthesis and activation of PI3K/Akt and MAPК signaling pathways in tumour tissue. Materials and Methods. The examination of the PR-A, PR-B, Akt, PTEN, ERK and Ki67 mRNAs expression in normal myometrium and leiomyoma tissues of 29 women with uterine leiomyoma was performed using RP-PCR. Results. It was found that in general the leiomyoma tissue was characterized by the high level of PR-A, PTEN and ERK mRNAs expression comparing to the miometrium. Distinctive characteristic of the small leiomyomas and leiomyomas with low proliferative activity was the highest synthesis of PR-A isoform of progesterone receptor. In large leiomyomas and in proliferating Ki67+ leiomymas the significant increase of ERK mRNA expression was seen. Conclusion. Activation of the PR-A isoform of progesterone receptor and MAPK/ERK signaling pathway associated with the inhibition of PI3K/Akt signaling due to high synthesis of PTEN plays the important role in mechanisms, regulating leiomyoma growth.

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“…1 As protein phosphorylation is a vital cellular process, its study is of utmost importance. The conformation, interaction partners, and the activity of many pathways are changed by the reversible and dynamic phosphorylation process.…”

Section: Introductionmentioning

confidence: 99%

Molecularly imprinted polymers synthesized via template immobilization on fumed silica nanoparticles for the enrichment of phosphopeptides

Duarte

Subedi

Yilmaz

et al. 2017

J of Molecular Recognition

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Phosphorylation is a protein post-translational modification (PTM) that plays an important role in cell signaling, cell differentiation, and metabolism. The hyper phosphorylated forms of certain proteins have been appointed as biomarkers for neurodegenerative diseases, and phosphorylationrelated mutations are important for detecting cancer pathways. Due to the low abundance of phosphorylated proteins in biological fluids, sample enrichment is beneficial prior to detection.Thus, a need to find new strategies for enriching phosphopeptides has emerged. Molecularly imprinted polymers (MIPs) are synthetic polymeric materials manufactured to exhibit affinity for a target molecule. In this study, MIPs have been synthesized using a new approach based on the use of fumed silica as sacrificial support acting as solid porogen with the template (phosphotyrosine) immobilized on its surface. Phosphotyrosine MIPs were tested against a mixture of peptides and phosphopeptides by performing micro-solid phase extraction using MIPs (μMISPE) packed in a pipette tip. First, the capability of the materials to preferentially enrich phosphopeptides was evaluated. In a next step, the enrichment of phosphopeptides from a whole-cell lysate of human embryonic kidney (HEK) 293T cells was performed. The eluates were analyzed using MALDI-MS in the first case and with nano-HPLC-ESI-MS/MS in the second case.The results showed that the MIPs provided affinity for phosphopeptides, binding preferentially to multi-site phosphorylated peptides. The MIPs could enrich phosphopeptides in over 10-fold compared with the number of phosphopeptides found in a cell lysate without enrichment. MS-based studies of protein phosphorylation are dependent on sample preparation steps that enrich the phosphorylated peptides prior to analysis.

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Protein Kinases and Phosphatases in the Control of Cell Fate

Cited by 249 publications

References 272 publications

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

Molecular mechanisms of regulation of uterine leiomyoma growth

Molecularly imprinted polymers synthesized via template immobilization on fumed silica nanoparticles for the enrichment of phosphopeptides

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