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Carboxy Terminus of Glucose Transporter 3 Contains an Apical Membrane Targeting Domain

Fourth Department of Internal Medicine (K.I., S.K.), Saitama Medical School, Saitama 350-0495, Japan; and Division of Molecular Metabolism and Diabetes (Y.O.), Department of Internal Medicine Tohoku University Graduate School of Medicine, Miyagi 980-8574, Japan; Institute for Molecular Bioscience (A.M.S., W.S.P., D.E.J.), University of Queensland, Brisbane 4072, Australia; and Garvan Institute of Medical Research (D.E.J.), St. Vincents Hospital, Sydney 2010, Australia

Address all correspondence and requests for reprints to: David E. James, Garvan Institute of Medical Research, St. Vincents Hospital, Sydney 2010, Australia. E-mail: d.james{at}garvan.org.au; or Yoshitomo Oka, Division of Molecular Metabolism and Diabetes, Department of Internal Medicine Tohoku University Graduate School of Medicine, Miyagi 980-8574, Japan. E-mail: oka{at}int3.med.tohoku.ac.jp.

We previously demonstrated that distinct facilitative glucose transporter isoforms display differential sorting in polarized epithelial cells. In Madin-Darby canine kidney (MDCK) cells, glucose transporter 1 and 2 (GLUT1 and GLUT2) are localized to the basolateral cell surface whereas GLUTs 3 and 5 are targeted to the apical membrane. To explore the molecular mechanisms underlying this asymmetric distribution, we analyzed the targeting of chimeric glucose transporter proteins in MDCK cells. Replacement of the carboxy-terminal cytosolic tail of GLUT1, GLUT2, or GLUT4 with that from GLUT3 resulted in apical targeting. Conversely, a GLUT3 chimera containing the cytosolic carboxy terminus of GLUT2 was sorted to the basolateral membrane. These findings are not attributable to the presence of a basolateral signal in the tails of GLUTs 1, 2, and 4 because the basolateral targeting of GLUT1 was retained in a GLUT1 chimera containing the carboxy terminus of GLUT5. In addition, we were unable to demonstrate the presence of an autonomous basolateral sorting signal in the GLUT1 tail using the low-density lipoprotein receptor as a reporter. By examining the targeting of a series of more defined GLUT1/3 chimeras, we found evidence of an apical targeting signal involving residues 473–484 (DRSGKDGVMEMN) in the carboxy tail. We conclude that the targeting of GLUT3 to the apical cell surface in MDCK cells is regulated by a unique cytosolic sorting motif.

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