Natural angiogenesis inhibitor signals through Erk5 activation of peroxisome proliferator-activated receptor gamma (PPARgamma).
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.
Biyashev
Dauren
D
Urology Department and RH Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Veliceasa
Dorina
D
Kwiatek
Angela
A
Sutanto
Maria M
MM
Cohen
Ronald N
RN
Volpert
Olga V
OV
D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
D020533:Angiogenesis Inhibitors; D005136:Eye Proteins; D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D016328:NF-kappa B; D009414:Nerve Growth Factors; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; C482563:MAP2K5 protein, human