Abstract
It is well established that widely expressed PTK7 is essential for vertebrate tissue morphogenesis. In cancer, the functionality of PTK7 is selectively regulated by membrane type-1 matrix metalloproteinase (MT1-MMP), ADAMs (a disintegrin domain and metalloproteinases), and γ-secretase proteolysis. Here, we established that the full-length membrane PTK7, its Chuzhoi mutant with the two functional MT1-MMP cleavage sites, and its L622D mutant with the single inactivated MT1-MMP cleavage site differentially regulate cell motility in a two-dimensional versus three-dimensional environment. We also demonstrated that in polarized cancer cells, the levels of PTK7 expression and proteolysis were directly linked to the structure and kinetics of cell protrusions, including lamellipodia and invadopodia. In the functionally relevant and widely accepted animal models of metastasis, mouse and chick embryo models, both the overexpression and knock-out of PTK7 in HT1080 cells abrogated metastatic dissemination. Our analysis of human tissue specimens confirmed intensive proteolysis of PTK7 in colorectal cancer tumors, but not in matching normal tissue. Our results provide convincing evidence that both PTK7 expression and proteolysis, rather than the level of the cellular full-length PTK7 alone, contribute to efficient directional cell motility and metastasis in cancer.
Highlights
In embryonic development, protein-tyrosine kinase 7 (PTK7) regulates orientation of cells in a tissue plane
We demonstrated that in polarized cancer cells, the levels of PTK7 expression and proteolysis were directly linked to the structure and kinetics of cell protrusions, including lamellipodia and invadopodia
The first cleavage caused the release of the soluble N-terminal PTK7– 65 ectodomain fragment and the generation of the matching cell-associated C-terminal PTK7–50 species was the result of membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis at the Pro-Lys-Pro2Leu622 site
Summary
PTK7 regulates orientation of cells in a tissue plane. Results: PTK7 controls cellular protrusions and, as a result, directional cell motility and metastasis in fibrosarcoma HT1080 cells. The functionality of PTK7 is selectively regulated by membrane type-1 matrix metalloproteinase (MT1-MMP), ADAMs (a disintegrin domain and metalloproteinases), and ␥-secretase proteolysis. Our results provide convincing evidence that both PTK7 expression and proteolysis, rather than the level of the cellular full-length PTK7 alone, contribute to efficient directional cell motility and metastasis in cancer. Because of extensive proteolysis and fragmentation of PTK7 leading to its multiple proteolytic fragments with contrasting functions, the current measurements of PTK7 in human cancer tissue specimens remain controversial. These measurements are predominantly based on semi-quantitative immunohistochemistry using a single PTK7 antibody and on measurements of PTK7 mRNA levels in tumor samples. We suggest that the MT1-MMP/PTK7 axis, rather than PTK7 alone, is a potential biomarker and a promising drug target in malignancies in which the MT1-MMP activity and PTK7 are co-expressed
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