Stimulus-dependent phosphorylation of profilin-1 in angiogenesis

Nat Cell Biol. 2012 Oct;14(10):1046-56. doi: 10.1038/ncb2580. Epub 2012 Sep 23.

Abstract

Angiogenesis, the formation of new blood vessels, is fundamental to development and post-injury tissue repair. Vascular endothelial growth factor (VEGF)-A guides and enhances endothelial cell migration to initiate angiogenesis. Profilin-1 (Pfn-1) is an actin-binding protein that enhances actin filament formation and cell migration, but stimulus-dependent regulation of Pfn-1 has not been observed. Here, we show that VEGF-A-inducible phosphorylation of Pfn-1 at Tyr 129 is critical for endothelial cell migration and angiogenesis. Chemotactic activation of VEGF receptor kinase-2 (VEGFR2) and Src induces Pfn-1 phosphorylation in the cell leading edge, promoting Pfn-1 binding to actin and actin polymerization. Conditional endothelial knock-in of phosphorylation-deficient Pfn1(Y129F) in mice reveals that Pfn-1 phosphorylation is critical for angiogenesis in response to wounding and ischaemic injury, but not for developmental angiogenesis. Thus, VEGFR2/Src-mediated phosphorylation of Pfn-1 bypasses canonical, multistep intracellular signalling events to initiate endothelial cell migration and angiogenesis, and might serve as a selective therapeutic target for anti-angiogenic therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Movement / physiology
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Female
  • Gene Knock-In Techniques
  • Ischemia / metabolism
  • Male
  • Mice
  • Microvessels / cytology
  • Microvessels / metabolism
  • Neovascularization, Physiologic
  • Phosphorylation
  • Profilins / genetics
  • Profilins / metabolism*
  • Signal Transduction / physiology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Wounds and Injuries / metabolism
  • src-Family Kinases / metabolism

Substances

  • Pfn1 protein, mouse
  • Profilins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • src-Family Kinases