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A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo.

Publication ,  Journal Article
Martin, NP; Marron Fernandez de Velasco, E; Mizuno, F; Scappini, EL; Gloss, B; Erxleben, C; Williams, JG; Stapleton, HM; Gentile, S; Armstrong, DL
Published in: Endocrinology
September 2014

Several rapid physiological effects of thyroid hormone on mammalian cells in vitro have been shown to be mediated by the phosphatidylinositol 3-kinase (PI3K), but the molecular mechanism of PI3K regulation by nuclear zinc finger receptor proteins for thyroid hormone and its relevance to brain development in vivo have not been elucidated. Here we show that, in the absence of hormone, the thyroid hormone receptor TRβ forms a cytoplasmic complex with the p85 subunit of PI3K and the Src family tyrosine kinase, Lyn, which depends on two canonical phosphotyrosine motifs in the second zinc finger of TRβ that are not conserved in TRα. When hormone is added, TRβ dissociates and moves to the nucleus, and phosphatidylinositol (3, 4, 5)-trisphosphate production goes up rapidly. Mutating either tyrosine to a phenylalanine prevents rapid signaling through PI3K but does not prevent the hormone-dependent transcription of genes with a thyroid hormone response element. When the rapid signaling mechanism was blocked chronically throughout development in mice by a targeted point mutation in both alleles of Thrb, circulating hormone levels, TRβ expression, and direct gene regulation by TRβ in the pituitary and liver were all unaffected. However, the mutation significantly impaired maturation and plasticity of the Schaffer collateral synapses on CA1 pyramidal neurons in the postnatal hippocampus. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases.

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Published In

Endocrinology

DOI

EISSN

1945-7170

ISSN

0013-7227

Publication Date

September 2014

Volume

155

Issue

9

Start / End Page

3713 / 3724

Related Subject Headings

  • src-Family Kinases
  • Thyroid Hormones
  • Thyroid Hormone Receptors beta
  • Synapses
  • Protein Transport
  • Protein Binding
  • Phosphorylation
  • Phosphatidylinositol 3-Kinases
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Martin, N. P., Marron Fernandez de Velasco, E., Mizuno, F., Scappini, E. L., Gloss, B., Erxleben, C., … Armstrong, D. L. (2014). A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology, 155(9), 3713–3724. https://doi.org/10.1210/en.2013-2058
Martin, Negin P., Ezequiel Marron Fernandez de Velasco, Fengxia Mizuno, Erica L. Scappini, Bernd Gloss, Christian Erxleben, Jason G. Williams, Heather M. Stapleton, Saverio Gentile, and David L. Armstrong. “A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo.Endocrinology 155, no. 9 (September 2014): 3713–24. https://doi.org/10.1210/en.2013-2058.
Martin NP, Marron Fernandez de Velasco E, Mizuno F, Scappini EL, Gloss B, Erxleben C, et al. A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology. 2014 Sep;155(9):3713–24.
Martin NP, Marron Fernandez de Velasco E, Mizuno F, Scappini EL, Gloss B, Erxleben C, Williams JG, Stapleton HM, Gentile S, Armstrong DL. A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology. 2014 Sep;155(9):3713–3724.
Journal cover image

Published In

Endocrinology

DOI

EISSN

1945-7170

ISSN

0013-7227

Publication Date

September 2014

Volume

155

Issue

9

Start / End Page

3713 / 3724

Related Subject Headings

  • src-Family Kinases
  • Thyroid Hormones
  • Thyroid Hormone Receptors beta
  • Synapses
  • Protein Transport
  • Protein Binding
  • Phosphorylation
  • Phosphatidylinositol 3-Kinases
  • Mice, Inbred C57BL
  • Mice