Identification of Regulatory Phosphorylation Sites in Mitogen-activated Protein Kinase (MAPK)-activated Protein Kinase-1a/p90   That Are Inducible by MAPK

Dalby, Kevin N.; Morrice, Nick; Caudwell, F. Barry; Avruch, Joseph; Cohen, Philip

doi:10.1074/jbc.273.3.1496

Cited by 345 publications

(398 citation statements)

References 34 publications

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“…It is known that p90 RSK1 is phosphorylated at S364 and T574 residues by ERKs, leading to its activation (Dalby et al, 1998), and our results on BAD phosphorylation imply that E 2 activates p90 RSK1 . Therefore, we directly determined that E 2 rapidly activates p90 RSK1 by in vitro kinase assay using immunoprecipitates of p90 RSK1 (Figure 6,D and E), which shows that p90 RSK1 is activated within 5 min by E 2 .…”

Section: Activation Of Erks By Estradiolmentioning

confidence: 49%

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

113

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Estrogens such as 17-β estradiol (E2) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E2 abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-α, H2O2, and serum starvation in causing apoptosis. Furthermore, the ability of E2 to prevent tumor necrosis factor-α-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90RSK1 and Akt, was not phosphorylated in response to E2 in vitro. E2 treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90RSK1 to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90RSK1 activation, E2 also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E2. Dominant negative Ras blocked E2-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E2-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E2-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E2 prevents apoptosis.

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Section: Activation Of Erks By Estradiolmentioning

confidence: 49%

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Fernando

Wimalasena

2004

MBoC

113

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“…The results showed that PG (10 µM) suppressed the activity of few protein kinases from a panel of 65 protein kinases encoded by the human genome. The proteins that were significantly inhibited (> 70%) were AKT, ribosomal S6 kinase (RSK)-2, mitogen and stress activated protein kinase (MSK)-1, serum glucocorticoid-inducible kinase (SGK)-1, calmodulin-dependent kinase (CaMK)-1 and Bruton´s tyrosine kinase (Btk) (29,30). All these proteins participate in PI3K/AKT/mTOR and MAPK pathways.…”

Section: Regulation Of Pi3k/akt/mtor and Mapk Pathways Is Mediated Bymentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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“…*P50.05, **P50.01 not due to changes in production (data not shown). It has been reported that ERK1/2 activate the p90 ribosomal S6 kinase (p90 RSK ) via phosphorylation (Dalby et al, 1998), and induce the activity of transcription factors to mediate various biological e ects (Dhanasekaven et al, 1998). Thus, we investigated whether p90 RSK was activated during CEC proliferation.…”

Section: Fgf2 But Not Vegf Is a Strong Mitogen For Cecmentioning

confidence: 99%

Two distinct signalling pathways are involved in FGF2-stimulated proliferation of choriocapillary endothelial cells: A comparative study with VEGF

et al. 2001

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Identification of Regulatory Phosphorylation Sites in Mitogen-activated Protein Kinase (MAPK)-activated Protein Kinase-1a/p90 That Are Inducible by MAPK

Cited by 345 publications

References 34 publications

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Two distinct signalling pathways are involved in FGF2-stimulated proliferation of choriocapillary endothelial cells: A comparative study with VEGF

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