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TSH/IGF-1 Receptor Cross-Talk Rapidly Activates Extracellular Signal-Regulated Kinases in Multiple Cell Types

Christine C Krieger1, Joseph D Perry1, Sarah J Morgan1

  • 1Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.

Endocrinology
|September 23, 2017
PubMed

Insights

Thyrotropin (TSH) and insulin-like growth factor-1 (IGF-1) receptor cross-talk synergistically activate ERK1/2 signaling in Graves

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Signaling

Background:

  • Thyrotropin (TSH)/insulin-like growth factor-1 (IGF-1) receptor cross-talk is implicated in Graves' orbitopathy (GO) pathogenesis.
  • TSH and IGF-1 synergistically increase hyaluronan secretion in GO orbital fibroblasts and sodium-iodide symporter expression in thyrocytes.
  • The precise mechanism of ERK1/2 activation in this synergism was previously unknown.

Purpose of the Study:

  • To investigate the role of ERK1/2 activation in the synergistic effects of TSH and IGF-1.
  • To determine if TSHR/IGF-1R cross-talk impacts ERK1/2 activation in GO fibroblasts and thyrocytes.
  • To elucidate the early signaling events involved in TSHR/IGF-1R synergism.

Main Methods:

  • Primary cultures of Graves' orbitopathy fibroblasts (GOFs) and human thyrocytes.
  • Human embryonic kidney (HEK) 293 cells overexpressing TSH receptors (HEK-TSHRs).
  • Analysis of ERK1/2 phosphorylation, pertussis toxin inhibition, and Gi/Go protein knockdown.

Main Results:

  • Simultaneous TSHR and IGF-1R activation caused rapid, synergistic ERK1/2 phosphorylation in GOFs, thyrocytes, and HEK-TSHRs.
  • This synergistic effect was partially inhibited by pertussis toxin, suggesting involvement of Gi/Go proteins.
  • Knockdown of Gi(1-3) and Go proteins inhibited TSH-stimulated ERK1/2 phosphorylation.

Conclusions:

  • TSHR/IGF-1R cross-talk triggers early synergistic ERK1/2 activation in the TSHR signaling cascade.
  • Gi/Go proteins play a role in mediating TSH-induced ERK1/2 phosphorylation.
  • This cross-talk mechanism is crucial for regulating GO fibroblasts and thyrocytes.

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