The VEGFR2 and PKA pathways converge at MEK/ERK1/2 to promote survival in serum deprived neuronal cells |
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Authors: | Evan Gomes Luena Papa Tianfeng Hao Patricia Rockwell |
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Institution: | (1) Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Ave, New York, NY 10021, USA |
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Abstract: | 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 mitogen in endothelial cells, can
mediate neuroprotection against damaging insults through the activation of its cognate receptor VEGFR2. In addition, growth
factor receptor signaling pathways have been shown to crosstalk with cAMP-dependent Protein Kinase A (PKA) to protect neuronal
cells from harmful stimuli. Whether a relationship exists between VEGFR2 and PKA in mediating neuroprotection under stressful
conditions is unknown. Using SK-N-SH neuronal cells as a model system, we show that serum deprivation induces an upregulation
in VEGF and VEGFR2 that concomitantly serves as a prosurvival signaling pathway. Inhibitor studies revealed that PKA functioned
concurrently with VEGFR2 pathway to signal the activation of the extracellular signal-regulated protein kinases (ERK1/2) as
protection against caspase-3/7 activation and a subsequent cell death. The loss in cell viability induced by VEGFR2 and PKA
inhibition was prevented by caspase inhibition or overexpression of ERK1. Overexpression of the antiapoptotic protein Bcl-xL
also promoted survival when VEGFR2 function was blocked. However, the protection elicited by all three treatments were prevented
by the inclusion of a selective inhibitor of mitogen-activated protein kinase kinase (MEK), the upstream kinase that activates
ERK1/2. Taken together, these findings suggested that PKA and VEGFR2 converge at the MEK/ERK1/2 pathway to protect serum starved
neuronal cells from a caspase-dependent cell death.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Vascular endothelial growth factor Neuronal cell survival Protein kinase A |
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