8 results on '"Bayascas JR"'
Search Results
2. Correction for Zurashvili et al., Interaction of PDK1 with Phosphoinositides Is Essential for Neuronal Differentiation but Dispensable for Neuronal Survival.
- Author
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Zurashvili T, Cordón-Barris L, Ruiz-Babot G, Zhou X, Lizcano JM, Gómez N, Giménez-Llort L, and Bayascas JR
- Published
- 2016
- Full Text
- View/download PDF
3. Fine-tuning the intensity of the PKB/Akt signal enables diverse physiological responses.
- Author
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Zhou X, Cordon-Barris L, Zurashvili T, and Bayascas JR
- Subjects
- Animals, Mice, Mice, Mutant Strains, Neurons metabolism, Phosphatidylinositols metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
The PI3K/PDK1/PKB signaling pathway plays essential roles in regulating neuronal survival, differentiation and plasticity in response to neurotrophic factors, neurotransmitters and ion channels. Both PDK1 and PKB can interact at the plasma membrane with a phosphoinositide synthesized by PI3K, the second messenger PtdIns(3,4,5)P3, enabling PDK1 to phosphorylate and activate PKB. In the PDK1 K465E knock-in mice expressing a mutant form of PDK1 incapable of phosphoinositide binding, activation of PKB was markedly affected, but not totally abolished. It has been recently proposed that in the absence of PtdIns(3,4,5)P3 binding, PDK1 can still moderately activate PKB due to a docking site-mediated interaction of these 2 kinases. A recent report has uncovered that in the PDK1 K465E mice neurons, a PKB signal threshold was sufficient to support neuronal survival responses, whereas neuritogenesis, neuronal polarization and axon outgrowth were severely impaired. We propose here that the low-efficiency mechanism of PKB activation observed in the PDK1 K465E mice might represent the ancestral mechanism responsible for the essential functions of this pathway, while the phosphoinositide-dependent activation should be considered an evolutionary innovation that enabled the acquisition of novel functions.
- Published
- 2014
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- View/download PDF
4. Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5 (ERK5) nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex.
- Author
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Erazo T, Moreno A, Ruiz-Babot G, Rodríguez-Asiain A, Morrice NA, Espadamala J, Bayascas JR, Gómez N, and Lizcano JM
- Subjects
- Animals, Cell Cycle Proteins biosynthesis, Cell Cycle Proteins genetics, Cell Line, Cell Proliferation, Chaperonins biosynthesis, Chaperonins genetics, HEK293 Cells, HeLa Cells, Humans, Mice, Mitogen-Activated Protein Kinase 7 genetics, Phosphorylation, RNA Interference, RNA, Small Interfering, Signal Transduction, Transcription, Genetic, Transcriptional Activation, Ubiquitination, Active Transport, Cell Nucleus, Cell Cycle Proteins metabolism, Cell Nucleus metabolism, Chaperonins metabolism, HSP90 Heat-Shock Proteins metabolism, Mitogen-Activated Protein Kinase 7 metabolism
- Abstract
The mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 5 (ERK5) plays a crucial role in cell proliferation, regulating gene transcription. ERK5 has a unique C-terminal tail which contains a transcriptional activation domain, and activates transcription by phosphorylating transcription factors and acting itself as a transcriptional coactivator. However, the molecular mechanisms that regulate its nucleocytoplasmatic traffic are unknown. We have used tandem affinity purification to identify proteins that interact with ERK5. We show that ERK5 interacts with the Hsp90-Cdc37 chaperone in resting cells, and that inhibition of Hsp90 or Cdc37 results in ERK5 ubiquitylation and proteasomal degradation. Interestingly, activation of cellular ERK5 induces Hsp90 dissociation from the ERK5-Cdc37 complex, leading to ERK5 nuclear translocation and activation of transcription, by a mechanism which requires the autophosphorylation at its C-terminal tail. Consequently, active ERK5 is no longer sensitive to Hsp90 or Cdc37 inhibitors. Cdc37 overexpression also induces Hsp90 dissociation and the nuclear translocation of a kinase-inactive form of ERK5 which retains transcriptional activity. This is the first example showing that ERK5 transcriptional activity does not require kinase activity. Since Cdc37 cooperates with ERK5 to promote cell proliferation, Cdc37 overexpression (as happens in some cancers) might represent a new, noncanonical mechanism by which ERK5 regulates tumor proliferation.
- Published
- 2013
- Full Text
- View/download PDF
5. Interaction of PDK1 with phosphoinositides is essential for neuronal differentiation but dispensable for neuronal survival.
- Author
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Zurashvili T, Cordón-Barris L, Ruiz-Babot G, Zhou X, Lizcano JM, Gómez N, Giménez-Llort L, and Bayascas JR
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases, Animals, Brain anatomy & histology, Brain cytology, Brain-Derived Neurotrophic Factor metabolism, Cell Survival, Cells, Cultured, Enzyme Activation, Gene Knock-In Techniques, Humans, Mice, Mutation, Neurons metabolism, Organ Size, Protein Binding, Protein Serine-Threonine Kinases chemistry, Protein Serine-Threonine Kinases genetics, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt metabolism, Ribosomal Protein S6 Kinases metabolism, Neurogenesis, Neurons cytology, Phosphatidylinositol Phosphates metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
3-Phosphoinositide-dependent protein kinase 1 (PDK1) operates in cells in response to phosphoinositide 3-kinase activation and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] production by activating a number of AGC kinases, including protein kinase B (PKB)/Akt. Both PDK1 and PKB contain pleckstrin homology (PH) domains that interact with the PtdIns(3,4,5)P(3) second messenger. Disrupting the interaction of the PDK1 PH domain with phosphoinositides by expressing the PDK1 K465E knock-in mutation resulted in mice with reduced PKB activation. We explored the physiological consequences of this biochemical lesion in the central nervous system. The PDK1 knock-in mice displayed a reduced brain size due to a reduction in neuronal cell size rather than cell number. Reduced BDNF-induced phosphorylation of PKB at Thr308, the PDK1 site, was observed in the mutant neurons, which was not rate limiting for the phosphorylation of those PKB substrates governing neuronal survival and apoptosis, such as FOXO1 or glycogen synthase kinase 3 (GSK3). Accordingly, the integrity of the PDK1 PH domain was not essential to support the survival of different embryonic neuronal populations analyzed. In contrast, PKB-mediated phosphorylation of PRAS40 and TSC2, allowing optimal mTORC1 activation and brain-specific kinase (BRSK) protein synthesis, was markedly reduced in the mutant mice, leading to impaired neuronal growth and differentiation.
- Published
- 2013
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6. Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation.
- Author
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Waugh C, Sinclair L, Finlay D, Bayascas JR, and Cantrell D
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases, Animals, Cell Differentiation, Cell Proliferation, Cell Survival, Cytotoxicity, Immunologic, Enzyme Activation, Forkhead Transcription Factors metabolism, Lymphocyte Activation, Mice, Models, Biological, Phosphorylation, Receptors, Lymphocyte Homing metabolism, Cell Movement, Phosphatidylinositols metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, T-Lymphocytes cytology, T-Lymphocytes enzymology
- Abstract
The present study explored the consequences of phosphoinositide (3,4,5)-triphosphate [PI(3,4,5)P(3)] binding to the pleckstrin homology (PH) domain of the serine/threonine kinase 3-phosphoinositide-dependent kinase 1 (PDK1). The salient finding is that PDK1 directly transduces the PI(3,4,5)P(3) signaling that determines T-cell trafficking programs but not T-cell growth and proliferation. The integrity of the PDK1 PH domain thus is not required for PDK1 catalytic activity or to support cell survival and the proliferation of thymic and peripheral T cells. However, a PDK1 mutant that cannot bind PI(3,4,5)P(3) cannot trigger the signals that terminate the expression of the transcription factor KLF2 in activated T cells and cannot switch the chemokine and adhesion receptor profile of naive T cells to the profile of effector T cells. The PDK1 PH domain also is required for the maximal activation of Akt/protein kinase B (PKB) and for the maximal phosphorylation and inactivation of Foxo family transcription factors in T cells. PI(3,4,5)P(3) binding to PDK1 and the strength of PKB activity thus can dictate the nature of the T-cell response. Low levels of PKB activity can be sufficient for T-cell proliferation but insufficient to initiate the migratory program of effector T cells.
- Published
- 2009
- Full Text
- View/download PDF
7. Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways.
- Author
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Bayascas JR
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases, Animals, Binding Sites, Insulin Resistance, Mice, Phenotype, Phosphatidylinositol Phosphates metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Serine-Threonine Kinases genetics, Protein Structure, Tertiary, Protein Serine-Threonine Kinases metabolism, Signal Transduction
- Abstract
The 3-phosphoinositide-dependent protein kinase-1 (PDK1) mediates the cellular effect of insulin and growth factors by activating a group of kinases including PKB/Akt, S6K, RSK, SGK and PKC isoforms. PDK1 possesses two regulatory domains namely a Pleckstrin Homology (PH) domain that binds to the phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P(3)] second messenger, and a substrate binding site termed the PIF-pocket. Employing a combination of biochemical, structural and mouse knock-in approaches we have been able to define the roles that the regulatory domains on PDK1 play. We have established that binding of PDK1 to PtdIns(3,4,5)P(3) is essential for efficient activation of PKB isoforms as well as for maintaining normal cell size and insulin sensitivity. In contrast, the PIF-substrate binding pocket of PDK1 is not required for PKB activation, but is necessary for PDK1 to activate all of its other substrates.
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- 2008
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- View/download PDF
8. Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance.
- Author
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Bayascas JR, Wullschleger S, Sakamoto K, García-Martínez JM, Clacher C, Komander D, van Aalten DM, Boini KM, Lang F, Lipina C, Logie L, Sutherland C, Chudek JA, van Diepen JA, Voshol PJ, Lucocq JM, and Alessi DR
- Subjects
- Amino Acid Substitution, Animals, Body Size physiology, Female, Insulin Resistance physiology, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Molecular, Mutagenesis, Site-Directed, Phenotype, Prediabetic State genetics, Prediabetic State metabolism, Protein Serine-Threonine Kinases chemistry, Protein Structure, Tertiary, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Body Size genetics, Insulin Resistance genetics, Mutation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-akt antagonists & inhibitors
- Abstract
PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.
- Published
- 2008
- Full Text
- View/download PDF
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