title: Thyrotropin and Insulin-Like Growth Factor 1 Receptor Crosstalk Upregulates Sodium-Iodide Symporter Expression in Primary Cultures of Human Thyrocytes.
abstract: Major regulation of thyroid gland function is mediated by thyrotropin (TSH) activating the TSH receptor (TSHR) and inducing upregulation of genes involved in thyroid hormone synthesis. Evidence suggests that the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) may play a role in regulating TSHR functional effects. This study examined the potential role of TSHR/IGF-1R crosstalk in primary cultures of human thyrocytes.
  
  
  
  TSH/IGF-1 co-treatment elicited additive effects on thyroglobulin (TG), thyroperoxidase (TPO), and deiodinase type 2 (DIO2) mRNA levels but synergistic effects on sodium-iodide symporter (NIS) mRNA. Similar cooperativity was seen on the level of TG protein secretion (additive) and NIS protein expression (synergistic). The IGF-1R tyrosine kinase inhibitor linsitinib inhibited TSH-stimulated upregulation of NIS but not TG, indicating that NIS regulation is in part IGF-1R dependent and occurs via receptor crosstalk. Cooperativity was not seen at the level of cAMP/protein kinase A (PKA) signaling, IGF-1R phosphorylation, or Akt activation. However, TSH and IGF-1 synergistically activated ERK1/2. Pharmacological inhibition of ERK1/2 by the MEK1/2 inhibitor U0126 and of Akt by MK-2206 virtually abolished NIS stimulation by TSH and the synergistic effect of IGF-1.
  
  
  
  As linsitinib inhibited upregulation of NIS stimulated by TSH alone, it is concluded that crosstalk between TSHR and IGF-1R, without agonist activation of IGF-1R, plays a role in NIS regulation in human thyrocytes via a mechanism involving ERK1/2 and/or Akt. Fully understanding the nature of this crosstalk has clinical implications for the treatment of thyroid diseases, including thyroid cancer.
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Morgan
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
authors.forename: Bernice
authors.initials: B
authors.lastname: Marcus-Samuels
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland.
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D027981:Symporters / Q000378:metabolism*; D000072637:Thyroid Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D000099209:Sodium-Iodide Symporters
chemical_list: D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D011989:Receptors, Thyrotropin; D027981:Symporters; D013972:Thyrotropin; D000099209:Sodium-Iodide Symporters
keywords: IGF-1R; TSHR; cAMP; sodium–iodide symporter