Natural angiogenesis inhibitor signals through Erk5 activation of peroxisome proliferator-activated receptor γ(PPARγ)

Dauren Biyashev, Dorina Veliceasa, Angela Kwiatek, Maria M. Sutanto, Ronald N. Cohen, Olga V. Volpert

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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-α 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 PPARγ transcription factor by displacement of SMRT co-repressor. PPARγ, in turn is critical for NFκB 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.

Original languageEnglish (US)
Pages (from-to)13517-13524
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number18
DOIs
StatePublished - Apr 30 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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