VEGFR2 and PKA converge at the MEK/ERK1 /2 pathway to promote survival in serum deprived neuronal cells.
Item
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Title
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VEGFR2 and PKA converge at the MEK/ERK1 /2 pathway to promote survival in serum deprived neuronal cells.
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Identifier
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AAI3278417
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identifier
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3278417
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Creator
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Gomes, Evan.
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Contributor
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Adviser: Patricia Rockwell
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Date
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2007
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Biology, Cell | Biology, Neuroscience
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Abstract
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Identifying prosurvival mechanisms in stressed neuronal cells would provide protective strategies to hinder neurodegeneration. Recent evidence shows that vascular endothelial growth factor (VEGF), a well established endothelial cell mitogen, can mediate neuroprotection through activation of its cognate receptor VEGFR2 in response to stressful stimuli. In addition, growth factor receptor signaling pathways have been shown to crosstalk with cAMP-dependent Protein Kinase A (PKA) to protect neuronal cells against harmful insults. Whether VEGFR2 and PKA cooperate to mediate neuronal cell survival under stress conditions is unknown. We show that serum deprivation induces an upregulation in VEGF and VEGFR2 that concomitantly serves as a signaling pathway to promote survival through activation of the extracellular signal-regulated protein kinases (ERK1/2). Studies revealed that the PKA and VEGFR2 signaling pathways converge at MEK/ERK1/2 as a protective mechanism against caspase-3/7 activation and a cell death that can be prevented by caspase inhibition or overexpression of ERK1. The loss in survival resulting from VEGFR2 inhibition was also accompanied by depleted levels of the antiapoptotic protein Bcl-xL; however, overexpression of Bcl-xL also prevented cell death. Nevertheless, treatments with an inhibitor of mitogen-activated protein kinase kinase (MEK), the upstream kinase that activates ERK1/2, reversed the protection elicited by caspase inhibition or overexpression of ERK1 or Bcl-xL. Furthermore, evidence suggests that VEGF mediates neuroprotection against a caspase activation that may involve regulation by the p38 mitogen activated protein kinase (MAPK) pathway. Herein, we show that inhibition of p38 MAPK augments the survival, the phosphorylation of Akt and ERK1/2 and the extent of caspase inhibition mediated by VEGF in serum starved neuronal cells. Inhibition of the VEGF receptor, VEGFR2, abrogated the protective effects induced by p38 MAPK inhibition in serum starved cells and re-established caspase activation, suggesting that p38 MAPK negatively regulates VEGF-mediated signaling of neuroprotection through VEGFR2. Collectively, these findings suggest that neuronal cell fate during starvation involves crosstalk between a prosurvival pathway directed by VEGFR2 and PKA that converge at MEK/ERK1/2 to prevent stressed neuronal cells from a caspase-dependent cell death. Additionally, VEGF signals protection against the activation of caspase-mediated cell death pathways induced by p38 MAPK-dependent and -independent mechanisms.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
