Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors

Fumihiko Furuya, Changxue Lu, Celine J. Guigon, Sheue Yann Cheng

Research output: Contribution to journalArticle

Abstract

Thyroid hormone (T3) is critical in growth, development, differentiation, and maintenance of metabolic homeostasis. Recent studies suggest that thyroid hormone receptors (TRs) not only mediate the biological activities of T3 via nucleus-initiated transcription, but also could act via nongenomic pathways. The striking phenotype of thyroid cancer exhibited by a knockin mutant mouse that harbors a dominant negative TRβ mutant (TRβPV/PV mouse) allows the elucidation of novel oncogenic activity of a TRβ mutant (PV) via extra-nuclear actions. PV physically interacts with the regulatory p85α subunit of phosphatidylinositol 3-kinase (PI3K) to activate the downstream AKT-mammalian target of rapamycin (mTOR) and p70S6K and PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathways. The PV-mediated PI3K activation results in increased cell proliferation, motility, migration, and metastasis. Remarkably, a nuclear receptor corepressor (NCoR) was found to regulate the PV-activated PI3K signaling by competing with PV for binding to the C-terminal SH2 domain of p85α. Over-expression of NCoR in thyroid tumor cells of TRβPV/PV mice reduces AKT-mTOR-p70S6K signaling. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells leads to over-activated PI3K-AKT signaling to increase cell proliferation and motility. Furthermore, NCoR protein levels are significantly lower in thyroid tumor cells than in wild type thyrocytes, allowing more effective binding of PV to p85α to activate PI3K signaling, thereby contributing to tumor progression. Thus, PV, an apo-TRβ, could act via direct protein-protein interaction to mediate critical oncogenic actions. These studies also uncovered a novel extra-nuclear role of NCoR in modulating the nongenomic actions of a mutated TRβ in controlling thyroid carcinogenesis.

Original languageEnglish (US)
Pages (from-to)628-634
Number of pages7
JournalSteroids
Volume74
Issue number7
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

Keywords

  • Mouse model
  • Nongenomic actions
  • Nuclear receptor corepressor
  • Phosphatidylinositol 3-kinase
  • Thyroid cancer
  • Thyroid hormone receptors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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