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Vol. 15, Issue 6, 2853-2862, June 2004

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Differential Trafficking of Transforming Growth Factor- Receptors and Ligand in Polarized Epithelial Cells

S. J. Murphy ^*, J. J. E. Doré , M. Edens ^*, R. J. Coffey , J. A. Barnard , H. Mitchell ^*, M. Wilkes ^*, and E. B. Leof ^* ||

^* Thoracic Diseases Research Unit, Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Division of Basic Medical Sciences, Memorial University of Newfoundland, St. Johns, Newfoundland A1B 3V6; Departments of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine and Nashville Veterans Association, Nashville, Tennessee 37232; and Center for Cell and Vascular Biology, Columbus Children's Institute, The Ohio State University College of Medicine, Columbus, Ohio 43210

Submitted February 4, 2004; Revised March 19, 2004; Accepted March 22, 2004
Monitoring Editor: Carl-Henrik Heldin

Epithelial cells in vivo form tight cell-cell associations that spatially separate distinct apical and basolateral domains. These domains provide discrete cellular processes essential for proper tissue and organ development. Using confocal imaging and selective plasma membrane domain activation, the type I and type II transforming growth factor- (TGF) receptors were found to be localized specifically at the basolateral surfaces of polarized Madin-Darby canine kidney (MDCK) cells. Receptors concentrated predominantly at the lateral sites of cell-cell contact, adjacent to the gap junctional complex. Cytoplasmic domain truncations for each receptor resulted in the loss of specific lateral domain targeting and dispersion to both the apical and basal domains. Whereas receptors concentrate basolaterally in regions of direct cell-cell contact in nonpolarized MDCK cell monolayers, receptor staining was absent from areas of noncell contact. In contrast to the defined basolateral polarity observed for the TGF receptor complex, TGF ligand secretion was found to be from the apical surfaces. Confocal imaging of MDCK cells with an antibody to TGF1 confirmed a predominant apical localization, with a stark absence at the basal membrane. These findings indicate that cell adhesion regulates the localization of TGF receptors in polarized epithelial cultures and that the response to TGF is dependent upon the spatial distribution and secretion of TGF receptors and ligand, respectively.

Abbreviations used: ECM, extracellular matrix; GM-CSF, granulocyte macrophage-colony stimulating factor; MDCK, Madin-Darby canine kidney; T1R, type I TGF receptor, T2R, type II TGF receptor; TGN, trans-Golgi network; TGF, transforming growth factor-.

^|| Corresponding author. E-mail address: leof.edward{at}mayo.edu.

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