title: Protein-tyrosine pseudokinase 7 (PTK7) directs cancer cell motility and metastasis.
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.
authors.affiliation: From the Sanford-Burnham Medical Research Institute, La Jolla, California 92037, vgolubkov@sanfordburnham.org.
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.affiliation: From the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Prigozhina
authors.affiliation: AntiCancer, Inc., San Diego, California 92111.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Department of Oncology, University of Alberta, Edmonton T6G 2E1, Canada.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Stoletov
authors.affiliation: the Department of Oncology, University of Alberta, Edmonton T6G 2E1, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: Protein Biotechnologies, Inc., Ramona, California 92065, and.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: AntiCancer, Inc., San Diego, California 92111, the Department of Surgery, University of California, San Diego, California 92103.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.affiliation: From the Sanford-Burnham Medical Research Institute, La Jolla, California 92037, strongin@sanfordburnham.org.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002642:Chick Embryo; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D009362:Neoplasm Metastasis; D059748:Proteolysis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D053511:Matrix Metalloproteinase 14
keywords: Cancer; Cell Polarity; Matrix Metalloproteinase (MMP); Metastasis; Migration; Protein Kinase