Proteolytic processing of laminin-5 by MT1-MMP in tissues and its effects on epithelial cell morphology.

Koshikawa N, Schenk S, Moeckel G, Sharabi A, Miyazaki K, Gardner H, Zent R, Quaranta V
FASEB J. 2004 18 (2): 364-6

PMID: 14688206 · DOI:10.1096/fj.03-0584fje

The extracellular matrix macromolecule laminin-5 (Ln-5) is converted by matrix metalloproteinases (MMP) MT1-MMP and MMP-2 into a migration-promoting substrate in vitro. We now report that cleavage of Ln-5 by MT1-MMP occurs in vivo and affects epithelial tissue organization and probably Ln-5 turnover. In MT1-MMP knockout (KO) mice, the kidneys showed increased levels of total Ln-5 gamma2 subunit, but significantly reduced amounts of gamma2', an amino-terminal truncated proteolytic form of gamma2. The kidney tubular epithelia of KO animals were poorly differentiated, a phenotype reminiscent of human congenital mixed hypoplastic/dysplastic disorders. To establish a better link between Ln-5 proteolytic cleavage and epithelial morphology, MT1-MMP expression was reconstituted by transfection of MT1-MMP into a Ln-5 positive, MT1-MMP deficient epithelial cell line. MT1-MMP transfectants demonstrated increased levels of processed Ln-5 gamma2 chain and enhanced spreading on Ln-5, but not fibronectin. Recombinant MT1-MMP cleaved gamma2 constructs in vitro at a known in vivo gamma2 gamma2' processing site. These results strongly indicate that Ln-5 is a physiological substrate of MT1-MMP in vivo. Proteolytic processing of gamma2 subunit by MT1-MMP may influence Ln-5 turnover in epithelial basement membranes and affect epithelial morphogenesis.

MeSH Terms (15)

Animals Cell Adhesion Molecules Cell Line Cell Movement Cell Size Epithelial Cells Kidney Matrix Metalloproteinase 14 Matrix Metalloproteinases, Membrane-Associated Metalloendopeptidases Mice Mice, Knockout Protein Processing, Post-Translational Protein Subunits Rats

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