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A New Mechanism for Prolactin Processing into 16K PRL by Secreted Cathepsin D

Institut National de la Santé et de la Recherche Médicale (INSERM), Unité (U) 808 (D.P., I.F., P.T., P.A.K., V.G.), F-75730 Paris Cedex 15, France; INSERM, U809 (N.B.), F-75730 Paris Cedex 15, France; Université Paris Descartes (D.P., I.F., N.B., P.T., P.A.K., V.G.), Faculté de Médecine René Descartes—Site Necker, F-75015 Paris, France; and Department of Endocrinology and Reproductive Medicine (P.T.), GH Pitié Salpêtrière Hospital, F-75651 Paris Cedex 13, France

Address all correspondence and requests for reprints to: Dr. Vincent Goffin, Institut National de la Santé et de la Recherche Médicale, Unité 808, Faculté de Médecine Necker, 156 rue de Vaugirard, Paris 75015, France. E-mail: goffin{at}necker.fr.

Cathepsins are lysosomal enzymes that were shown to release the antiangiogenic fragments 16K prolactin (PRL), 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 PRL into 16K PRL outside the cell. To specifically target extracellular proteolysis, we used tissues from PRL receptor-deficient mice, which are unable to internalize PRL. 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 antiangiogenic 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 antiangiogenic peptides in nonpathological contexts.

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