Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution.

Schenk S, Hintermann E, Bilban M, Koshikawa N, Hojilla C, Khokha R, Quaranta V
J Cell Biol. 2003 161 (1): 197-209

PMID: 12695504 · PMCID: PMC2172889 · DOI:10.1083/jcb.200208145

Extracellular matrix (ECM) fragments or cryptic sites unmasked by proteinases have been postulated to affect tissue remodeling and cancer progression. Therefore, the elucidation of their identities and functions is of great interest. Here, we show that matrix metalloproteinases (MMPs) generate a domain (DIII) from the ECM macromolecule laminin-5. Binding of a recombinant DIII fragment to epidermal growth factor receptor stimulates downstream signaling (mitogen-activated protein kinase), MMP-2 gene expression, and cell migration. Appearance of this cryptic ECM ligand in remodeling mammary gland coincides with MMP-mediated involution in wild-type mice, but not in tissue inhibitor of metalloproteinase 3 (TIMP-3)-deficient mice, supporting physiological regulation of DIII liberation. These findings indicate that ECM cues may operate via direct stimulation of receptor tyrosine kinases in tissue remodeling, and possibly cancer invasion.

MeSH Terms (24)

Animals Basement Membrane Breast Breast Neoplasms Carcinoma Cell Adhesion Molecules Cell Movement Cells, Cultured Epidermal Growth Factor Epithelial Cells ErbB Receptors Extracellular Matrix Proteins Female Matrix Metalloproteinase 2 Matrix Metalloproteinases Mice Mice, Knockout Mitogen-Activated Protein Kinases Neoplasm Invasiveness Peptide Fragments Protein Binding Protein Structure, Tertiary Receptor Protein-Tyrosine Kinases Tissue Inhibitor of Metalloproteinase-3

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