HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marinò, M. Articles by McCluskey, R. T. Search for Related Content PubMed PubMed Citation Articles by Marinò, M. Articles by McCluskey, R. T. Social Bookmarking                      What's this?

J Biol Chem, Vol. 275, Issue 10, 7125-7137, March 10, 2000

Role of Megalin (gp330) in Transcytosis of Thyroglobulin by Thyroid Cells
A NOVEL FUNCTION IN THE CONTROL OF THYROID HORMONE RELEASE^*

Michele Marinò^§¶, Gang Zheng, Luca Chiovato^§, Aldo Pinchera^§, Dennis Brown, David Andrews, and Robert T. McCluskey

From the  Pathology Research Laboratory and the  Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and the ^§ Department of Endocrinology, University of Pisa, Pisa, Italy 56124

When thyroglobulin (Tg) is endocytosed by thyrocytes and transported to lysosomes, thyroid hormones (T4 and T3) are released. However, some internalized Tg is transcytosed intact into the bloodstream, thereby avoiding proteolytic cleavage. Here we show that megalin (gp330), a Tg receptor on thyroid cells, plays a role in Tg transcytosis. Following incubation with exogenous rat Tg at 37 °C, Fisher rat thyroid (FRTL-5) cells, a differentiated thyroid cell line, released T3 into the medium. However, when cells were incubated with Tg plus either of two megalin competitors, T3 release was increased, suggesting that Tg internalized by megalin bypassed the lysosomal pathway, possibly with release of undegraded Tg from cells. To assess this possibility, we performed experiments in which FRTL-5 cells were incubated with either unlabeled or ¹²⁵I-labeled Tg at 37 °C to allow internalization, treated with heparin to remove cell surface-bound Tg, and further incubated at 37 °C to allow Tg release. Intact 330-kDa Tg was released into the medium, and the amount released was markedly reduced by megalin competitors. To investigate whether Tg release resulted from transcytosis, we studied FRTL-5 cells cultured as polarized layers with tight junctions on permeable filters in the upper chamber of dual chambered devices. Following the addition of Tg to the upper chamber and incubation at 37 °C, intact 330-kDa Tg was found in fluids collected from the lower chamber. The amount recovered was markedly reduced by megalin competitors, indicating that megalin mediates Tg transcytosis. We also studied Tg transcytosis in vivo, using a rat model of goiter induced by aminotriazole, in which increased release of thyrotropin induces massive colloid endocytosis. This was associated with increased megalin expression on thyrocytes and increased serum Tg levels, with reduced serum T3 levels, supporting the conclusion that megalin mediates Tg transcytosis. Tg transcytosis is a novel function of megalin, which usually transports ligands to lysosomes. Megalin-mediated transcytosis may regulate the extent of thyroid hormone release.

---

^* This work was supported by NIDDK, National Institutes of Health Grants 46301 (to R. T. M.) and DK42956 (D. B.); by Grants from the National Research Council (Consiglio Nazionale Ricerche, Roma, Italy) (Target Project Biotechnology and Bioinstrumentation Grant 91.01219 and Target Project Prevention and Control of Disease Factors Grant 93.00437); and by EEC Stimulation Action-Science Plan Contract SC1-CT91-0707.

^¶ Recipient of an American Thyroid Association research grant for 1999. To whom correspondence should be addressed: Pathology Research Laboratory, Massachusetts General Hospital, Harvard Medical School, 149 13th St., Charlestown, MA 02129. Tel.: 617-726-5690; Fax: 617-726-5684; E-mail: m.marino@endoc.med.unipi.it.

---

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				M. J. Rowling, C. M. Kemmis, D. A. Taffany, and J. Welsh Megalin-Mediated Endocytosis of Vitamin D Binding Protein Correlates with 25-Hydroxycholecalciferol Actions in Human Mammary Cells J. Nutr., November 1, 2006; 136(11): 2754 - 2759. [Abstract] [Full Text] [PDF]

				M. Conte, A. Arcaro, D. D'Angelo, A. Gnata, G. Mamone, P. Ferranti, S. Formisano, and F. Gentile A Single Chondroitin 6-Sulfate Oligosaccharide Unit at Ser-2730 of Human Thyroglobulin Enhances Hormone Formation and Limits Proteolytic Accessibility at the Carboxyl Terminus: POTENTIAL INSIGHTS INTO THYROID HOMEOSTASIS AND AUTOIMMUNITY J. Biol. Chem., August 4, 2006; 281(31): 22200 - 22211. [Abstract] [Full Text] [PDF]

				H. Birn The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins Am J Physiol Renal Physiol, July 1, 2006; 291(1): F22 - F36. [Abstract] [Full Text] [PDF]

				S. Lisi, R. Botta, A. Pinchera, A. B. Collins, S. Refetoff, P. Arvan, G. Bu, L. Grasso, V. Marshansky, S. Bechoua, et al. Defective thyroglobulin storage in LDL receptor-associated protein-deficient mice Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1160 - C1167. [Abstract] [Full Text] [PDF]

				M.-F. van den Hove, K. Croizet-Berger, F. Jouret, S. E. Guggino, W. B. Guggino, O. Devuyst, and P. J. Courtoy The Loss of the Chloride Channel, ClC-5, Delays Apical Iodide Efflux and Induces a Euthyroid Goiter in the Mouse Thyroid Gland Endocrinology, March 1, 2006; 147(3): 1287 - 1296. [Abstract] [Full Text] [PDF]

				B. Erranz, J. F. Miquel, W. S. Argraves, J. L. Barth, F. Pimentel, and M.-P. Marzolo Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids J. Lipid Res., December 1, 2004; 45(12): 2185 - 2198. [Abstract] [Full Text] [PDF]

				P. R. Cutillas, R. J. Chalkley, K. C. Hansen, R. Cramer, A. G. W. Norden, M. D. Waterfield, A. L. Burlingame, and R. J. Unwin The urinary proteome in Fanconi syndrome implies specificity in the reabsorption of proteins by renal proximal tubule cells Am J Physiol Renal Physiol, September 1, 2004; 287(3): F353 - F364. [Abstract] [Full Text] [PDF]

				W. S. Prince, L. M. McCormick, D. J. Wendt, P. A. Fitzpatrick, K. L. Schwartz, A. I. Aguilera, V. Koppaka, T. M. Christianson, M. C. Vellard, N. Pavloff, et al. Lipoprotein Receptor Binding, Cellular Uptake, and Lysosomal Delivery of Fusions between the Receptor-associated Protein (RAP) and {alpha}-L-Iduronidase or Acid {alpha}-Glucosidase J. Biol. Chem., August 13, 2004; 279(33): 35037 - 35046. [Abstract] [Full Text] [PDF]

				S. Lisi, A. Pinchera, R. T. McCluskey, T. E. Willnow, S. Refetoff, C. Marcocci, P. Vitti, F. Menconi, L. Grasso, F. Luchetti, et al. Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: A control mechanism for thyroid hormone release PNAS, December 9, 2003; 100(25): 14858 - 14863. [Abstract] [Full Text] [PDF]

				D. M. Kamikura and J. A. Cooper Lipoprotein receptors and a Disabled family cytoplasmic adaptor protein regulate EGL-17/FGF export in C. elegans Genes & Dev., November 15, 2003; 17(22): 2798 - 2811. [Abstract] [Full Text] [PDF]

				P. L. TUMA and A. L. HUBBARD Transcytosis: Crossing Cellular Barriers Physiol Rev, July 1, 2003; 83(3): 871 - 932. [Abstract] [Full Text] [PDF]

				P. J. Verroust and E. I. Christensen Megalin and cubilin--the story of two multipurpose receptors unfolds Nephrol. Dial. Transplant., November 1, 2002; 17(11): 1867 - 1871. [Full Text] [PDF]

				M. Marino, L. Chiovato, S. Lisi, A. Pinchera, and R. T. McCluskey Binding of the Low Density Lipoprotein Receptor-Associated Protein (RAP) to Thyroglobulin (Tg): Putative Role of RAP in the Tg Secretory Pathway Mol. Endocrinol., October 1, 2001; 15(10): 1829 - 1837. [Abstract] [Full Text] [PDF]

				M. MARINO, D. ANDREWS, D. BROWN, and R. T. McCLUSKEY Transcytosis of Retinol-Binding Protein across Renal Proximal Tubule Cells after Megalin (gp 330)-Mediated Endocytosis J. Am. Soc. Nephrol., April 1, 2001; 12(4): 637 - 648. [Abstract] [Full Text] [PDF]

				E. I. Christensen and H. Birn Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule Am J Physiol Renal Physiol, April 1, 2001; 280(4): F562 - F573. [Abstract] [Full Text] [PDF]

				M. Marino and R. T. McCluskey Role of thyroglobulin endocytic pathways in the control of thyroid hormone release Am J Physiol Cell Physiol, November 1, 2000; 279(5): C1295 - C1306. [Abstract] [Full Text] [PDF]

				F. Martin-Belmonte, M. A. Alonso, X. Zhang, and P. Arvan Thyroglobulin Is Selected as Luminal Protein Cargo for Apical Transport via Detergent-resistant Membranes in Epithelial Cells J. Biol. Chem., December 22, 2000; 275(52): 41074 - 41081. [Abstract] [Full Text] [PDF]

				J. C. Obunike, E. P. Lutz, Z. Li, L. Paka, T. Katopodis, D. K. Strickland, K. F. Kozarsky, S. Pillarisetti, and I. J. Goldberg Transcytosis of Lipoprotein Lipase across Cultured Endothelial Cells Requires Both Heparan Sulfate Proteoglycans and the Very Low Density Lipoprotein Receptor J. Biol. Chem., March 16, 2001; 276(12): 8934 - 8941. [Abstract] [Full Text] [PDF]