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Molecular and Cellular Biology, April 1999, p. 3136-3144, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Basolateral Sorting of Furin in MDCK Cells Requires a Phenylalanine-Isoleucine Motif Together with an Acidic Amino Acid Cluster

Thomas Simmen,1 Massimo Nobile,1 Juan S. Bonifacino,2 and Walter Hunziker1,*

Institute of Biochemistry, BIL Biomedical Research Center, University of Lausanne, CH-1066 Epalinges, Switzerland,1 and Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 208922

Received 14 August 1998/Returned for modification 29 September 1998/Accepted 7 January 1999

Furin is a subtilisin-related endoprotease which processes a wide range of bioactive proteins. Furin is concentrated in the trans-Golgi network (TGN), where proteolytic activation of many precursor proteins takes place. A significant fraction of furin, however, cycles among the TGN, the plasma membrane, and endosomes, indicating that the accumulation in the TGN reflects a dynamic localization process. The cytosolic domain of furin is necessary and sufficient for TGN localization, and two signals are responsible for retrieval of furin to the TGN. A tyrosine-based (YKGL) motif mediates internalization of furin from the cell surface into endosomes. An acidic cluster that is part of two casein kinase II phosphorylation sites (SDSEEDE) is then responsible for retrieval of furin from endosomes to the TGN. In addition, the acidic EEDE sequence also mediates endocytic activity. Here, we analyzed the sorting of furin in polarized epithelial cells. We show that furin is delivered to the basolateral surface of MDCK cells, from where a significant fraction of the protein can return to the TGN. A phenylalanine-isoleucine motif together with the acidic EEDE cluster is required for basolateral sorting and constitutes a novel signal regulating intracellular traffic of furin.

* Corresponding author. Mailing address: Institute of Biochemistry, BIL Biomedical Research Center, University of Lausanne, CH-1066 Epalinges, Switzerland. Phone: 41 21 692 5737. Fax: 41 21 692 5705. E-mail: Walter.Hunziker{at}ib.unil.ch.

Molecular and Cellular Biology, April 1999, p. 3136-3144, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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