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RECEPTORS AND SIGNAL TRANSDUCTION

L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase

¹The Signal Transduction Laboratory, Ordway Research Institute, ²Albany Medical College, and ³Pharmaceutical Research Institute, Albany College of Pharmacy, Albany, New York; and ⁴Department of Biology, University of Rome "Roma Tre," Rome, Italy

Submitted 10 June 2008 ; accepted in final form 16 January 2009

3,5,3'-Triiodo-L-thyronine (T₃), but not L-thyroxine (T₄), activated Src kinase and, downstream, phosphatidylinositol 3-kinase (PI3-kinase) by means of an _vβ₃ integrin receptor on human glioblastoma U-87 MG cells. Although both T₃ and T₄ stimulated extracellular signal-regulated kinase (ERK) 1/2, activated ERK1/2 did not contribute to T₃-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 T₃ and T₄. Thus the PI3-kinase, Src kinase, and ERK1/2 signaling cascades are parallel pathways in T₃-treated U-87 MG cells. T₃ and T₄ 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 T₃ on U-87 MG cells. PI3-kinase-dependent actions of T₃ in these cells included shuttling of nuclear thyroid hormone receptor- (TR) from cytoplasm to nucleus and accumulation of hypoxia-inducible factor (HIF)-1 mRNA; LY-294002 inhibited these actions. Results of studies involving _vβ₃ receptor antagonists tetraiodothyroacetic acid (tetrac) and Arg-Gly-Asp (RGD) peptide, together with mathematical modeling of the kinetics of displacement of radiolabeled T₃ from the integrin by unlabeled T₃ and by unlabeled T₄, are consistent with the presence of two iodothyronine receptor domains on the integrin. A model proposes that one site binds T₃ exclusively, activates PI3-kinase via Src kinase, and stimulates TR trafficking and HIF-1 gene expression. Tetrac and RGD peptide both inhibit T₃ action at this site. The second site binds T₄ and T₃, and, via this receptor, the iodothyronines stimulate ERK1/2-dependent tumor cell proliferation. T₃ action here is inhibited by tetrac alone, but the effect of T₄ is blocked by both tetrac and the RGD peptide.

thyroid hormone; phosphatidylinositol 3-kinase; extracellular signal-regulated kinase 1/2; integrin _vβ₃; glioblastoma cells; Src kinase; mitogen-activated protein kinase; intracellular hormone receptor trafficking

This article has been cited by other articles:

				P. J. Davis, F. B. Davis, H.-Y. Lin, S. A. Mousa, M. Zhou, and M. K. Luidens Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor Am J Physiol Endocrinol Metab, December 1, 2009; 297(6): E1238 - E1246. [Abstract] [Full Text] [PDF]

				M. Bhargava, J. Lei, and D. H. Ingbar Nongenomic actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine. Focus on "L-Thyroxine vs. 3,5,3'-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase" Am J Physiol Cell Physiol, May 1, 2009; 296(5): C977 - C979. [Full Text] [PDF]