L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: Activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

Hung Yun Lin, Mingzeng Sun, Heng Yuan Tang, Cassie Lin, Mary K. Luidens, Shaker A. Mousa, Sandra Incerpi, George L. Drusano, Faith B. Davis, Paul J. Davis

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225 Citations (Scopus)


3,5,3′-Triiodo-L-thyronine (T 3), but not L-thyroxine (T 4), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an α vβ 3 integrin receptor on human glioblastoma U-87 MG cells. Although both T 3 and T 4 stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T 3-induced Src kinase or PI3-kinase activation, and an inhibitor of PI3-kinase, LY-294002, did not block activation of ERK1/2 by physiological concentrations of T 3 and T 4. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T 3-treated U-87 MG cells. T 3 and T 4 both caused proliferation of U-87 MG cells; these effects were blocked by the ERK1/2 inhibitor PD-98059 but not by LY-294002. Small-interfering RNA knockdown of PI3-kinase confirmed that PI3-kinase was not involved in the proliferative action of T 3 on U-87 MG cells. PI3-kinase-dependent actions of T 3 in these cells included shuttling of nuclear thyroid hormone receptor-α (TRα) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1α mRNA; LY-294002 inhibited these actions. Results of studies involving α vβ 3 receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T 3 from the integrin by unlabeled T 3 and by unlabeled T 4, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T 3 exclusively, activates PI3-kinase via Src kinase, and stimulates TRα trafficking and HIF-1α gene expression. Tetrac and RGD peptide both inhibit T 3 action at this site. The second site binds T 4 and T 3, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T 3 action here is inhibited by tetrac alone, but the effect of T 4 is blocked by both tetrac and the RGD peptide.

Original languageEnglish
Pages (from-to)C980-C991
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
Publication statusPublished - May 2009
Externally publishedYes


  • Extracellular signal-regulated kinase 1/2
  • Glioblastoma cells
  • Integrin α β
  • Intracellular hormone receptor trafficking
  • Mitogen-activated protein kinase
  • Phosphatidylinositol 3-kinase
  • Src kinase
  • Thyroid hormone

ASJC Scopus subject areas

  • Cell Biology
  • Physiology


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