Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures

Mol Cell Biol. 2010 Apr;30(7):1593-606. doi: 10.1128/MCB.00038-09. Epub 2010 Feb 1.

Abstract

Endothelial cell (EC) migration, cell-cell adhesion, and the formation of branching point structures are considered hallmarks of angiogenesis; however, the underlying mechanisms of these processes are not well understood. Lipid phosphate phosphatase 3 (LPP3) is a recently described p120-catenin-associated integrin ligand localized in adherens junctions (AJs) of ECs. Here, we tested the hypothesis that LPP3 stimulates beta-catenin/lymphoid enhancer binding factor 1 (beta-catenin/LEF-1) to induce EC migration and formation of branching point structures. In subconfluent ECs, LPP3 induced expression of fibronectin via beta-catenin/LEF-1 signaling in a phosphatase and tensin homologue (PTEN)-dependent manner. In confluent ECs, depletion of p120-catenin restored LPP3-mediated beta-catenin/LEF-1 signaling. Depletion of LPP3 resulted in destabilization of beta-catenin, which in turn reduced fibronectin synthesis and deposition, which resulted in inhibition of EC migration. Accordingly, reexpression of beta-catenin but not p120-catenin in LPP3-depleted ECs restored de novo synthesis of fibronectin, which mediated EC migration and formation of branching point structures. In confluent ECs, however, a fraction of p120-catenin associated and colocalized with LPP3 at the plasma membrane, via the C-terminal cytoplasmic domain, thereby limiting the ability of LPP3 to stimulate beta-catenin/LEF-1 signaling. Thus, our study identified a key role for LPP3 in orchestrating PTEN-mediated beta-catenin/LEF-1 signaling in EC migration, cell-cell adhesion, and formation of branching point structures.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Catenins / genetics
  • Catenins / metabolism
  • Cell Adhesion / physiology
  • Cell Line
  • Cell Movement / physiology*
  • Delta Catenin
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology*
  • Fibronectins / metabolism
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Molecular Sequence Data
  • Neovascularization, Physiologic*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • RNA Interference
  • Signal Transduction / physiology
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Catenins
  • Fibronectins
  • Isoenzymes
  • Lymphoid Enhancer-Binding Factor 1
  • beta Catenin
  • PLPP3 protein, human
  • Phosphatidate Phosphatase
  • PTEN Phosphohydrolase
  • Delta Catenin
  • CTNND1 protein, human