Thyroid hormone receptor TRβ1 mediates Akt activation by T3 in pancreatic β cells

Abstract

It has recently been recognized that thyroid hormones may rapidly generate biological responses by non-genomic mechanisms that are unaffected by inhibitors of transcription and translation. The signal transduction pathways underlying these effects are just beginning to be defined. We demonstrated that thyroid hormone T 3 rapidly induces Akt activation in pancreatic b cells rRINm5F and hCM via thyroid hormone receptor (TR) b1. The phosphorylation of Akt was T 3 specific and dependent. Coimmunoprecipitation and colocalization experiments revealed that the phosphatidylinositol 3 kinase (PI3K) p85a subunit and the thyroid receptor b1 were able to form a complex at the cytoplasmic level in both the cell lines, suggesting that a 'cytoplasmic TRb1' was implicated. Moreover, we evidenced that T 3 treatment was able to induce kinase activity of the TRb1-associated PI3K. The silencing of TRb1 expression through RNAi confirmed this receptor to be crucial for the T 3 -induced activation of Akt. This action involved a T 3 -induced nuclear translocation of activated Akt, as demonstrated by confocal immunofluorescence. In summary, T 3 is able to specifically activate Akt in the islet b cells rRINm5F and hCM through the interaction between TRb1 and PI3K p85a, demonstrating the involvement of TRb1 in this novel T 3 non-genomic action in islet b cells.

Thyroid Disorders in Patients of Type 2 Diabetes Mellitus

“…This may be related to an association between higher FT3 levels, and decreased HbA1c i.e. low total T3 [22,23].…”

Nuclear Factor (NF)-κB-dependent Thyroid Hormone Receptor β1 Expression Controls Dendritic Cell Function via Akt Signaling

“…Once activated, pAkt is translocated to different cell compartments, including the nucleus (10). Immunoblot analysis of pAkt in the nuclear fraction of DCs revealed the ability of T 3 to trigger rapid recruitment of pAkt (Ser-473) to the nucleus following exposure to T 3 (Fig.…”

“…Several cytoplasmic T 3 actions mediated by TR are linked to activation of the PI3K pathway in alveolar cells (7) and human fibroblasts (8). Moreover, activation of Akt, a critical component of cell growth and survival (9), has been detected in pancreatic islet ␤ cells upon engagement of TR␤ 1 and activation of PI3K-p85 (10).…”

The significance of TRIP11 and T3 signaling pathway in renal cancer progression and survival of patients.

“…1). We hypothesised that this T3 effect could be mediated by PI3K, previously shown to be activated by thyroid hormone [20,21]. To test this hypothesis, we pre-treated the cells with specific PI3K inhibitor, wortmannin.…”

“…T3 activates PI3K pathway by two mechanisms: either by THRB-mediated activation of p85α PI3K subunit in the cytoplasm [21] or by the mechanisms involving the membrane receptor, integrin αvβ3 [23]. To test the latter possibility, Caki-2 cells were cultured in the presence of T3-agarose, which precludes intracellular T3 actions.…”