The Wnt/planar cell polarity (PCP) protein tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase (MT1-MMP): implications in cancer and embryogenesis

Golubkov, V.S., Chekanov, A.V., Cieplak, P., Aleshin, A.E., Chernov, A.V., Zhu, W., Radichev, I.A., Zhang, D., Dong, P.D., and Strongin, A.Y.
The Journal of biological chemistry   285(46): 35740-35749 (Journal)
Registered Authors
Dong, P. Duc, Zhang, Danhua
Breast cancer, Cell surface receptor, Metalloprotease, Proteolytic enzymes, Wnt pathway, Zebra fish, MT1-MMP, PTK7
MeSH Terms
  • Animals
  • Binding Sites/genetics
  • Cell Adhesion Molecules/chemistry
  • Cell Adhesion Molecules/genetics
  • Cell Adhesion Molecules/metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement
  • Cell Polarity
  • Cytoskeleton/metabolism
  • Embryo, Nonmammalian/embryology*
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Humans
  • In Situ Hybridization
  • Matrix Metalloproteinase 14/genetics
  • Matrix Metalloproteinase 14/metabolism*
  • Molecular Sequence Data
  • Mutation
  • Neoplasms/genetics
  • Neoplasms/metabolism
  • Neoplasms/pathology
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptor Protein-Tyrosine Kinases/chemistry
  • Receptor Protein-Tyrosine Kinases/genetics
  • Receptor Protein-Tyrosine Kinases/metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transfection
  • Wnt Proteins/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
20837484 Full text @ J. Biol. Chem.
PTK7 is an essential component of the Wnt/PCP pathway. We provide evidence that the Wnt/PCP pathway converges with pericellular proteolysis in both normal development and cancer. Here, we demonstrate that MT1-MMP, a key pro-invasive proteinase, functions as a principal sheddase of PTK7. MT1-MMP directly cleaves the exposed PKP621-LI sequence of the seventh Ig-like domain of the full-length membrane PTK7 and generates, as a result, an N-terminal, soluble PTK7 species (sPTK7). The enforced expression of membrane PTK7 in cancer cells leads to the actin cytoskeleton re-organization and the inhibition of cell invasion. MT1-MMP silencing and the analysis of the uncleavable L622D PTK7 mutant confirm the significance of MT1-MMP proteolysis of PTK7 in cell functions. Our data also demonstrate that a fine balance between the metalloproteinase activity and PTK7 levels is required for normal development of zebrafish (Danio rerio). Aberration of this balance by the proteinase inhibition or PTK7 silencing results in the PCP-dependent convergent extension (CE) defects in the zebrafish. Overall, our data suggest that the MT1-MMP-PTK7 axis plays an important role both in cancer cell invasion and normal embryogenesis in vertebrates. Further insight into these novel mechanisms may promote understanding of directional cell motility and lead to the identification of therapeutics to treat PCP-related developmental disorders and malignancy.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes