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Endocytosis of a chimera between human pro-urokinase and the plant toxin saporin: an unusual internalization mechanism

RODOLFO IPPOLITI^*1, EUGENIO LENDARO^*, PIER ALBERTO BENEDETTI, MARIA ROSARIA TORRISI, FRANCESCA BELLEUDI, DANIELA CARPANI^§, MARCO RAFFAELLO SORIA^§ and MARIA SERENA FABBRINI^§

^* Department of Biochemical Sciences ‘A. Rossi Fanelli’, University of Rome La Sapienza, Rome, Italy;
C.N.R. Institute of Biophysics, Pisa, Italy;
Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy; and
^§ DIBIT, Department of Biological and Technological Research-DIBIT, S. Raffaele Scientific Institute, Milano, Italy

¹Correspondence: Department of Biochemical Sciences, University of Rome ‘La Sapienza’, P.le Aldo Moro 5, 00185 Rome, Italy. E-mail: rodolfo.ippoliti{at}uniroma1.it

A fluorescent derivative of a chimeric toxin between human pro-urokinase and the plant ribosome-inactivating protein saporin (p-uPA-Sap_TRITC), has been prepared in order to study the endocytosis of this potentially antimetastatic conjugate in the murine model cell line LB6 clone19 (Cl19) transfected with the human urokinase receptor gene. The physiological internalization of urokinase-inhibitor complexes is triggered by the interaction of plasminogen inhibitors (PAIs) with receptors belonging to the low density lipoprotein-related receptor protein (LRP) family, and involves a macro-quaternary structure including uPAR, LRP, and PAIs. However, in contrast to this mechanism, we observed a two-step process: first, the urokinase receptor (uPAR) acts as the anchoring factor on the plasma membrane; subsequently, LRP acts as the endocytic trigger. Once the chimera is bound to the plasma membrane by interaction with uPAR, we suggest that a possible exchange may occur to transfer the toxin to LRP via the saporin moiety and begin the internalization. So an unusual endocytic process is described, where the toxin enters the cell via a receptor different from that used to bind the plasma membrane.—Ippoliti, R., Lendaro, E., Benedetti, P. A., Torrisi, M. R., Belleudi, F., Carpani, D., Soria, M. R., Fabbrini, M. S. Endocytosis of a chimera between human pro-urokinase and the plant toxin saporin: an unusual internalization mechanism.

Key Words: plasminogen activator • ribosome-inactivating proteins • receptors • ligand-passing • cancer

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