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

作者：Furuya Fumihiko; Lu Changxue; Guigon Celine J; Cheng Sheue Yann^*

来源：Steroids, 2009, 74(7): 628-634.

DOI：10.1016/j.steroids.2008.10.009

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

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 TR beta mutant (TR beta(PV/PV) mouse) allows the elucidation of novel oncogenic activity of a TR beta mutant (PV) via extra-nuclear actions. PV physically interacts with the regulatory p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K) to activate the downstream AKT-mammalian target of rapamycin (mTOR) and p70(S6K) 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 p85 alpha. Over-expression of NCoR in thyroid tumor cells of TR beta(PV/PV) mice reduces AKT-mTOR-p70(S6K) 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 p85 alpha to activate PI3K signaling, thereby contributing to tumor progression. Thus, PV, an apo-TR beta, could act via direct protein-protein interaction to mediate critical oncogenic actions. These studies also uncovered a novel extranuclear role of NCoR in modulating the nongenomic actions of a mutated TR beta in controlling thyroid carcinogenesis. Published by Elsevier Inc.

• 出版日期2009-7