Insights into ectodomain shedding and processing of protein-tyrosine pseudokinase 7 (PTK7)

J Biol Chem. 2012 Dec 7;287(50):42009-18. doi: 10.1074/jbc.M112.371153. Epub 2012 Oct 24.


The membrane PTK7 pseudokinase, a component of both the canonical and noncanonical/planar cell polarity Wnt pathways, modulates cell polarity and motility in biological processes as diverse as embryo development and cancer cell invasion. To determine the individual proteolytic events and biological significance of the ectodomain shedding in the PTK7 function, we used highly invasive fibrosarcoma HT1080 cells as a model system. Current evidence suggested a likely link between PTK7 shedding and cell invasion in our HT1080 cell model system. We also demonstrated that in HT1080 cells the cleavage of the PTK7 ectodomain by an ADAM proteinase was coupled with the membrane type-1 matrix metalloproteinase (MT1-MMP) cleavage of the PKP(621)↓LI site in the seventh Ig-like domain of PTK7. Proteolytic cleavages led to the generation of two soluble, N-terminal and two matching C-terminal, cell-associated fragments of PTK7. This proteolysis was a prerequisite for the intramembrane cleavage of the C-terminal fragments of PTK7 by γ-secretase. γ-Secretase cleavage was predominantly followed by the efficient decay of the resulting C-terminal PTK7 fragment via the proteasome. In contrast, in HT1080 cells, which overexpressed the C-terminal PTK7 fragment, the latter readily entered the nucleus. Our data imply that therapeutic inhibition of PTK7 shedding may be used to slow cancer progression.

Publication types

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

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • Active Transport, Cell Nucleus / genetics
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line, Tumor
  • Fibrosarcoma / enzymology
  • Fibrosarcoma / genetics
  • Fibrosarcoma / pathology
  • Humans
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Neoplasm Invasiveness
  • Protein Structure, Tertiary
  • Proteolysis*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Solubility


  • Cell Adhesion Molecules
  • PTK7 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • Matrix Metalloproteinase 14