Abstract
Follicular thyroglobulin (TG) decreases expression of the thyroid-restricted transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, thereby suppressing expression of the sodium iodide symporter, thyroid peroxidase, TG, and thyrotropin receptor genes (Suzuki, K., Lavaroni, S., Mori, A., Ohta, M., Saito, J., Pietrarelli, M., Singer, D. S., Kimura, S., Katoh, R., Kawaoi, A. , and Kohn, L. D. (1997) Proc. Natl. Acad. Sci. U. S. A. 95, 8251-8256). The ability of highly purified 27, 19, or 12 S follicular TG to suppress thyroid-restricted gene expression correlates with their ability to bind to FRTL-5 thyrocytes and is inhibited by a specific antibody to the thyroid apical membrane asialoglycoprotein receptor (ASGPR), which is related to the ASGPR of liver cells. Phosphorylating serine/threonine residues of TG, by autophosphorylation or protein kinase A, eliminates TG suppression and enhances transcript levels of the thyroid-restricted genes 2-fold in the absence of a change in TG binding to the ASGPR. Follicular TG suppression of thyroid-restricted genes is thus mediated by the ASPGR on the thyrocyte apical membrane and regulated by a signal system wherein phosphorylation of serine/threonine residues on the bound ligand is an important component. These data provide a hitherto unsuspected role for the ASGPR in transcriptional signaling, aside from its role in endocytosis. They establish a functional role for phosphorylated serine/threonine residues on the TG molecule.
Highlights
Thyrotropin (TSH),1 in concert with insulin and insulin-like growth factor-1 (IGF-1), regulates thyroid function [1,2,3]
TG Suppression by the ASGPR Is Phosphorylation-regulated related to their ability to bind to the ASGPR, which has been separately located on the apical membrane of thyrocytes
The Action of TG to Suppress Thyroid-restricted Gene Expression Involves Binding to the ASPGR on the Apical Membrane—In our previous reports [17,18,19], we used highly purified 19 S follicular TG to evaluate its suppressive effect on TG, thyroid peroxidase (TPO), and NIS gene expression in rat FRTL-5 thyroid cells and on suppression of TTF-1, Pax-8, and TTF-2, the thyroid-restricted transcription factors that control TG, TPO, and NIS expression in thyrocytes
Summary
Thyrotropin (TSH), in concert with insulin and insulin-like growth factor-1 (IGF-1), regulates thyroid function [1,2,3]. It has been suggested that newly synthesized TG attaches to a specific binding protein related to the lectinlike asialoglycoprotein receptor (ASPGR) of the liver [22,23,24,25,26]2 and that the thyroid ASPGR vectorially transports newly synthesized TG to the follicular lumen [22,23,24,25] During this vectorial transport process, TG undergoes posttranslational modifications, including phosphorylation, (21, 25, 28 –32). We suggest that follicular TG acts as a regulator of thyroid-restricted gene expression by binding to the ASGPR on the apical thyrocyte membrane and that phosphorylation of TG regulates the suppressive effect. The data are the first to describe a role for the ASGPR in transcriptional signaling and a biologic role for phosphorylated TG, its phosphoserine residues
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