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-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.
Ulianich
L
L
Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Suzuki
K
K
Mori
A
A
Nakazato
M
M
Pietrarelli
M
M
Goldsmith
P
P
Pacifico
F
F
Consiglio
E
E
Formisano
S
S
Kohn
L D
LD
D000818:Animals; D037263:Asialoglycoprotein Receptor; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D005805:Genes, MHC Class I / Q000187:drug effects; D007453:Iodide Peroxidase / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins; D013489:Suppression, Genetic; D013954:Thyroglobulin / Q000737:chemistry / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
D037263:Asialoglycoprotein Receptor; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D010768:Phosphoserine; D019319:Okadaic Acid; D013954:Thyroglobulin; D007453:Iodide Peroxidase