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MBC in Press, published online ahead of print May 16, 2007
Mol. Biol. Cell 10.1091/mbc.E06-10-0912

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Submitted on October 12, 2006
Revised on April 24, 2007
Accepted on May 3, 2007

Urokinase Receptor Cleavage: a Crucial Step in Fibroblast to Myofibroblast Differentiation

Audrey M. Bernstein,* Sally S. Twining,{dagger} Debra J. Warejcka,{dagger} Edward Tall,* and Sandra K. Masur*{ddagger}

Departments of *Ophthalmology and {ddagger}Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029; {dagger}Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226

Monitoring Editor: M. Bishr Omary

Fibroblasts migrate into and repopulate connective tissue wounds. At the wound edge, fibroblasts differentiate into myofibroblasts and promote wound closure. Regulated fibroblast to myofibroblast differentiation is critical for regenerative healing. Previous studies have focused on the role in fibroblasts of uPA/uPAR (urokinase plasmingen activator/receptor), an extracellular protease system that promotes matrix remodeling, growth factor activation, and cell migration. Whereas fibroblasts have substantial uPA activity and uPAR expression, we discovered that cultured myofibroblasts eventually lost cell-surface uPA/uPAR. This led us to investigate the relevance of uPA/uPAR activity to myofibroblast differentiation. We found that fibroblasts expressed increased amounts of full-length cell-surface uPAR (D1D2D3) compared with myofibroblasts, which had reduced expression of D1D2D3 but increased expression of the truncated form of uPAR (D2D3) on their cell-surface. Retaining full-length uPAR was found to be essential for regulating myofibroblast differentiation since 1) protease inhibitors that prevented uPAR cleavage, also prevented myofibroblast differentiation and 2) overexpression of cDNA for a noncleavable form of uPAR inhibited myofibroblast differentiation. These data support a novel hypothesis that maintaining full-length uPAR on the cell surface regulates the fibroblast to myofibroblast transition and that down-regulation of uPAR is necessary for myofibroblast differentiation.

Address correspondence to: Audrey M. Bernstein (audrey.bernstein{at}mssm.edu)




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Extracellular matrix dynamics in development and regenerative medicine
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[Abstract] [Full Text] [PDF]


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