Abstract
Erk-5, a member of the MAPK superfamily, has a catalytic domain similar to Erk1/2 and a unique C-terminal domain enabling binding with transcription factors. Aberrant vascularization in the Erk5-null mice suggested a link to angiogenesis. Ectopic expression of constitutively active Erk5 blocks endothelial cell morphogenesis and causes HIF1-alpha destabilization/degradation. However the mechanisms by which endogenous Erk5 regulates angiogenesis remain unknown. We show that Erk5 and its activating kinase MEK5 are the upstream mediators of the anti-angiogenic signal by the natural angiogenesis inhibitor, pigment epithelial-derived factor (PEDF). We demonstrate that Erk5 phosphorylation allows activation of PPARgamma transcription factor by displacement of SMRT co-repressor. PPARgamma, in turn is critical for NFkappaB activation, PEDF-dependent apoptosis, and anti-angiogenesis. The dominant negative MEK5 mutant and Erk5 shRNA diminished PEDF-dependent apoptosis, inhibition of the endothelial cell chemotaxis, and angiogenesis. This is the first evidence of Erk5-dependent transduction of signals by endogenous angiogenesis inhibitors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Angiogenesis Inhibitors / metabolism*
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Angiogenesis Inhibitors / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Endothelial Cells / metabolism*
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Eye Proteins / genetics
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Eye Proteins / metabolism*
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Female
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Humans
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MAP Kinase Kinase 5 / genetics
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MAP Kinase Kinase 5 / metabolism
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / physiology*
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 7 / genetics
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Mitogen-Activated Protein Kinase 7 / metabolism*
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Mutation
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Nuclear Receptor Co-Repressor 2 / genetics
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Nuclear Receptor Co-Repressor 2 / metabolism
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Serpins / genetics
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Serpins / metabolism*
Substances
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Angiogenesis Inhibitors
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Eye Proteins
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NCOR2 protein, human
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NF-kappa B
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Ncor2 protein, mouse
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Nerve Growth Factors
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Nuclear Receptor Co-Repressor 2
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PPAR gamma
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Serpins
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pigment epithelium-derived factor
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Mitogen-Activated Protein Kinase 7
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MAP Kinase Kinase 5
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MAP2K5 protein, human