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© The Rockefeller University Press, 0021-9525/1997//1719 $5.00
The Journal of Cell Biology, Volume 139, Number 7, , 1997 1719-1733

Article

Cytoskeletal Protein ABP-280 Directs the Intracellular Trafficking of Furin and Modulates Proprotein Processing in the Endocytic Pathway



Gseping Liu*, Laurel Thomas*, Robin A. Warren{ddagger}, Caroline A. Enns{ddagger}, C. Casey Cunningham§, John H. Hartwig§, and Gary Thomas*,{ddagger},§

* Vollum Institute and {ddagger} Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201; and § Division of Experimental Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Furin catalyzes the proteolytic maturation of many proproteins within the trans-Golgi network (TGN)/endosomal system. Furin's cytosolic domain (cd) directs both the compartmentalization to and transit between its manifold processing compartments (i.e., TGN/biosynthetic pathway, cell surface, and endosomes). Here we report the identification of the first furin cd sorting protein, ABP-280 (nonmuscle filamin), an actin gelation protein. The furin cd was used as bait in a yeast two-hybrid screen to identify ABP-280 as a furin-binding protein. Binding analyses in vitro and coimmunoprecipitation studies in vivo showed that furin and ABP-280 interact directly and that ABP-280 tethers furin molecules to the cell surface. Quantitative analysis of both ABP-280-deficient and genetically replete cells showed that ABP-280 modulates the rate of internalization of furin but not of the transferrin receptor, a cycling receptor. However, although ABP-280 directs the rate of furin internalization, the efficiency of sorting of the endoprotease from the cell surface to early endosomes is independent of expression of ABP-280. By contrast, efficient sorting of furin from early endosomes to the TGN requires expression of ABP-280. In addition, ABP-280 is also required for the correct localization of late endosomes (dextran bead uptake) and lysosomes (LAMP-1 staining), demonstrating a pleiotropic role for this actin binding protein in the organization of cellular compartments and directing protein traffic. Finally, and consistent with the trafficking studies on furin, we showed that ABP-280 modulates the processing of furin substrates in the endocytic but not the biosynthetic pathways. The novel roles of ABP-280 and the cytoskeleton in the sorting of furin in the TGN/ endosomal system and the formation of proprotein processing compartments are discussed.

Abbreviations used in this paper: {alpha}2MR/LRP, macroglobulin receptors/ low density lipoprotein receptor-related protein; cd, cytosolic domain; PE, Pseudomonas exotoxin; Tf, transferrin; TGN, trans-Golgi network; TXR, Texas red.

This was supported by National Institutes of Health (NIH) grants DK-37274 and DK-44629 (G. Thomas) and DK-40608 (C.A. Enns). G. Liu was supported by NIH Training Grants DK-07680 and DK-07674, and also National Research Service Award. DK-09394.

Address all correspondence to Gary Thomas, Vollum Institute and Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, OR 97201. Tel.: 503-494-6955. Fax: 503-494-4534. E-mail: thomasg{at}ohsu.edu


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