title: Potential relation of aberrant proteolysis of human protein tyrosine kinase 7 (PTK7) chuzhoi by membrane type 1 matrix metalloproteinase (MT1-MMP) to congenital defects.
abstract: Membrane PTK7 pseudo-kinase plays an essential role in planar cell polarity and the non-canonical Wnt pathway in vertebrates. Recently, a new N-ethyl-N-nitrosourea-induced mutant named chuzhoi (chz) was isolated in mice. chz embryos have severe birth defects, including a defective neural tube, defective heart and lung development, and a shortened anterior-posterior body axis. The chz mutation was mapped to the Ala-Asn-Pro tripeptide insertion into the junction region between the fifth and the sixth Ig-like domains of PTK7. Unexpectedly, chz reduced membrane localization of the PTK7 protein. We hypothesized and then proved that the chz mutation caused an insertion of an additional membrane type 1 matrix metalloproteinase cleavage site in PTK7 and that the resulting aberrant proteolysis of chz affected the migratory parameters of the cells. It is likely that aberrations in the membrane type 1 matrix metalloproteinase/PTK7 axis are detrimental to cell movements that shape the body plan and that chz represents a novel model system for increasing our understanding of the role of proteolysis in developmental pathologies, including congenital defects.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Aleshin
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000201:enzymology* / Q000235:genetics; D000477:Alkylating Agents / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects / Q000235:genetics; D005038:Ethylnitrosourea / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000477:Alkylating Agents; D015815:Cell Adhesion Molecules; C507096:Mmp14 protein, mouse; C096905:PTK7 protein, human; C486452:Ptk7 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D005038:Ethylnitrosourea