Nemo-like kinase regulates the expression of vascular endothelial growth factor (VEGF) in alveolar epithelial cells

Sci Rep. 2016 Apr 1:6:23987. doi: 10.1038/srep23987.

Abstract

The canonical Wnt signaling can be silenced either through β-catenin-mediated ubiquitination and degradation or through phosphorylation of Tcf and Lef by nemo-like kinase (NLK). In the present study, we generated NLK deficient animals and found that these mice become cyanotic shortly before death because of lung maturation defects. NLK-/- lungs exhibited smaller and compressed alveoli and the mesenchyme remained thick and hyperplastic. This phenotype was caused by epithelial activation of vascular endothelial growth factor (VEGF) via recruitment of Lef1 to the promoter of VEGF. Elevated expression of VEGF and activation of the VEGF receptor through phosphorylation promoted an increase in the proliferation rate of epithelial and endothelial cells. In summary, our study identifies NLK as a novel signaling molecule for proper lung development through the interconnection between epithelial and endothelial cells during lung morphogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / cytology*
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Enzyme-Linked Immunosorbent Assay
  • Exons
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Genes, Reporter
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lung / embryology
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • Phenotype
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • Wnt Signaling Pathway*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Lef1 protein, mouse
  • Lymphoid Enhancer-Binding Factor 1
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • NLK protein, human
  • Nlk protein, mouse
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases