Journal
JOURNAL OF CELL BIOLOGY
Volume 161, Issue 1, Pages 197-209Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200208145
Keywords
ECM; MMP-2 gene expression; microarray; receptor tyrosme; kinase; TIMP-3 knockout mouse
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Funding
- NCI NIH HHS [R01 CA047858, CA47858] Funding Source: Medline
- NIGMS NIH HHS [GM46902] Funding Source: Medline
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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 (Dill) from the ECM macromolecule laminin-5. Binding of a recombinant Dill 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 Dill 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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