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Submitted on January 25, 2006
Accepted on August 28, 2006
Inserm U808, F-75730 Paris Cedex 15, France; Inserm U809, F-75730 Paris Cedex 15, France; Université Paris Descartes, Faculté de Médecine René Descartes - site Necker, F-75015 Paris, France; Department of Endocrinology and Reproductive Medicine, Pitié Salpêtrière Hospital, F-75651 Paris Cedex 13, France
* To whom correspondence should be addressed. E-mail: goffin{at}necker.fr.
Cathepsins are lysosomal enzymes that were shown to release the anti-angiogenic fragments 16K prolactin, endostatin and angiostatin by processing precursors at acidic pH in vitro. However, the physiological relevance of these findings is questionable because the neutral pH of physiological fluids is not compatible with the acidic conditions required for the proteolytic activity of these enzymes. Here we show that cathepsin D secreted from various tissues is able to process prolactin into 16K prolactin outside the cell. To specifically target extracellular proteolysis, we used tissues from prolactin receptor deficient mice, which are unable to internalize prolactin. As assessed by the use of specific inhibitors of proton extruders, we show that the proteolytic activity of cathepsin D requires local acid secretion driven by Na+/H+ exchangers and H+/ATPase. Although it is usually assumed that cathepsin-mediated generation of anti-angiogenic peptides occurs in the moderately acidic pericellular milieu found in malignant tumors, we propose a new mechanism explaining the extracellular activity of this acidic protease under physiological pH. Our data support the concept that secreted lysosomal enzymes could be involved in the maintenance of angiogenesis dormancy via the generation of active anti-angiogenic peptides in non pathological contexts.
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