Thyroid-hormone-dependent activation of the phosphoinositide 3-kinase/Akt cascade requires Src and enhances neuronal survival

We have reported previously a non-genomic action of T 3 (3,3',5-tri-iodothyronine), which stimulates the PI3K (phosphoinositide 3-kinase)/Akt pathway via p85α, the regulatory subunit of PI3K, in human skin fibroblasts. The aim of the present study was to elucidate the mechanism by which T 3 activates PI3K, and to investigate the physiological role of this T 3 action in neuronal cells. We found that T 3 activates PI3K/Akt through Src. First, T 3 rapidly induced the activation of Src and Akt in N2a cells expressing TRα 1 (thyroid hormone receptor α1; N2aTRα), and both were attenuated by either the addition of a Src inhibitor or Src siRNA. In contrast, a PI3K inhibitor could only block the activation of Akt. Secondly, T 3 enhanced TRα 1 ―p85α―Src complex formation, which was also abrogated by a Src inhibitor. The activation of Src and PI3K/Akt contributes to the anti-apoptotic effect of T 3 in N2aTRα cells. Moreover, it was also observed in primary cerebral cortical neurons that T 3 induced the activation of PI3K/Akt and suppressed serum-deprivation-induced apoptosis. Together, the findings of the present study demonstrate a novel non-genomic action of T 3 on neuronal cell survival, and provide new insights into the mechanism underlying this action, which involves Src activation and TRα1―p85α―Src complex formation.