Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution.
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.
Schenk
Susann
S
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. sschenk@scripps
Hintermann
Edith
E
Bilban
Martin
M
Koshikawa
Naohiko
N
Hojilla
Carlo
C
Khokha
Rama
R
Quaranta
Vito
V
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D066246:ErbB Receptors / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000235:genetics; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D016326:Extracellular Matrix Proteins; D020778:Matrix Metalloproteinase 2; D020782:Matrix Metalloproteinases; D020928:Mitogen-Activated Protein Kinases; D010446:Peptide Fragments; D020794:Receptor Protein-Tyrosine Kinases; D019717:Tissue Inhibitor of Metalloproteinase-3; D000097794:Kalinin