Follicular thyroglobulin (TG) suppression of thyroid-restricted genes involves the apical membrane asialoglycoprotein receptor and TG phosphorylation

Follicular thyroglobulin (TG) decreases expression of the thyroid-restricte d transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and P ax-8, thereby suppressing expression of the sodium iodide symporter, thyroi d 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 follicul ar TG to suppress thyroid-restricted gene expression correlates with their ability to bind to FRTL-5 thyrocytes and is inhibited by a specific antibod y to the thyroid apical membrane asialoglycoprotein receptor (ASGPR), which is related to the ASGPR of liver cells. Phosphorylating serine/threonine r esidues of TG, by autophosphorylation or protein kinase A, eliminates TG su ppression 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 s uppression of thyroid-restricted genes is thus mediated by the ASPGR on the thyrocyte apical membrane and regulated by a signal system wherein phospho rylation of serine/threonine residues on the bound ligand is an important c omponent. These data provide a hitherto unsuspected role for the ASGPR in t ranscriptional signaling, aside from its role in endocytosis. They establis h a functional role for phosphorylated serine/threonine residues on the TG molecule.