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Published 14 April 2003. doi:10.1083/jcb.200208145
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© The Rockefeller University Press, 0021-9525/2003/4/197 $5.00
The Journal of Cell Biology, Volume 161, Number 1, 197-209

Article

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

Susann Schenk1, Edith Hintermann1, Martin Bilban1, Naohiko Koshikawa1, Carlo Hojilla2, Rama Khokha2 and Vito Quaranta1

1 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9

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: sschenk{at}scripps.edu; 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: quaranta{at}scripps.edu

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.

Key Words: ECM; MMP-2 gene expression; microarray; receptor tyrosine kinase; TIMP-3 knockout mouse

* 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.


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