title: Lipid phosphate phosphatase 3 stabilization of beta-catenin induces endothelial cell migration and formation of branching point structures.
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.
authors.affiliation: Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Humtsoe
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Wary
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D005353:Fibronectins; D007527:Isoenzymes; D051821:Lymphoid Enhancer-Binding Factor 1; D051176:beta Catenin; C521833:PLPP3 protein, human; D010711:Phosphatidate Phosphatase; D051059:PTEN Phosphohydrolase; D000095002:Delta Catenin; C000722347:CTNND1 protein, human