Document Detail


The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis.
MedLine Citation:
PMID:  20837484     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PTK7 is an essential component of the Wnt/planar cell polarity (PCP) pathway. We provide evidence that the Wnt/PCP pathway converges with pericellular proteolysis in both normal development and cancer. Here, we demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP), a key proinvasive proteinase, functions as a principal sheddase of PTK7. MT1-MMP directly cleaves the exposed PKP(621)↓LI sequence of the seventh Ig-like domain of the full-length membrane PTK7 and generates, as a result, an N-terminal, soluble PTK7 fragment (sPTK7). The enforced expression of membrane PTK7 in cancer cells leads to the actin cytoskeleton reorganization 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 defects in the zebrafish. Overall, our data suggest that the MT1-MMP-PTK7 axis plays an important role in both 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.
Authors:
Vladislav S Golubkov; Alexei V Chekanov; Piotr Cieplak; Alexander E Aleshin; Andrei V Chernov; Wenhong Zhu; Ilian A Radichev; Danhua Zhang; P Duc Dong; Alex Y Strongin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-08     Completed Date:  2011-02-09     Revised Date:  2014-04-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  35740-9     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GENBANK/GU211905
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites / genetics
Cell Adhesion Molecules / chemistry,  genetics,  metabolism*
Cell Line
Cell Line, Tumor
Cell Movement
Cell Polarity
Cytoskeleton / metabolism
Embryo, Nonmammalian / embryology*,  metabolism
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Humans
In Situ Hybridization
Matrix Metalloproteinase 14 / genetics,  metabolism*
Molecular Sequence Data
Mutation
Neoplasms / genetics,  metabolism,  pathology
Protein Binding
Protein Structure, Tertiary
Receptor Protein-Tyrosine Kinases / chemistry,  genetics,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Transfection
Wnt Proteins / metabolism
Zebrafish / embryology,  genetics,  metabolism
Zebrafish Proteins / chemistry,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA77470/CA/NCI NIH HHS; CA83017/CA/NCI NIH HHS; P30 CA030199/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Wnt Proteins; 0/Zebrafish Proteins; EC 2.7.1.-/PTK7 protein, human; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 3.4.24.80/Matrix Metalloproteinase 14
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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