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.
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14 April 2003
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April 14 2003
Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution
Susann Schenk,
Susann Schenk
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
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Edith Hintermann,
Edith Hintermann
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
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Martin Bilban,
Martin Bilban
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
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Naohiko Koshikawa,
Naohiko Koshikawa
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
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Carlo Hojilla,
Carlo Hojilla
2Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9
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Rama Khokha,
Rama Khokha
2Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9
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Vito Quaranta
Vito Quaranta
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
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Susann Schenk
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
Edith Hintermann
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
Martin Bilban
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
Naohiko Koshikawa
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
Carlo Hojilla
2Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9
Rama Khokha
2Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9
Vito Quaranta
1Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
Address correspondence to Susann Schenk, The Scripps Research Institute, 10550 North Torrey Pines Road, Mail-Drop VB-1, La Jolla, CA 92037. Tel.: (858) 784-7191. Fax: (858) 784-7333. E-mail: [email protected]; or Vito Quaranta, The Scripps Research Institute, 10550 North Torrey Pines Road, Mail-Drop SBR-12, La Jolla, CA 92037. Tel.: (858) 784-2907. Fax: (858) 784-2246. E-mail: [email protected]
*
Abbreviations used in this paper: AR, amphiregulin; BM, basement membrane; EGFR, epidermal growth factor receptor; ERK, extracellular signal–regulated kinase; LE, laminin-type EGF; Ln-1, laminin-1; Ln-5, laminin-5; MMP, matrix metalloproteinase; rDIII, recombinant DIII; RTK, receptor tyrosine kinase; TIMP-3, tissue inhibitor of metalloproteinase 3; WT, wild-type.
Received:
August 23 2002
Revision Received:
February 20 2003
Accepted:
February 20 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 161 (1): 197–209.
Article history
Received:
August 23 2002
Revision Received:
February 20 2003
Accepted:
February 20 2003
Citation
Susann Schenk, Edith Hintermann, Martin Bilban, Naohiko Koshikawa, Carlo Hojilla, Rama Khokha, Vito Quaranta; Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution . J Cell Biol 14 April 2003; 161 (1): 197–209. doi: https://doi.org/10.1083/jcb.200208145
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