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 T3 (3,3',5-tri-iodothyronine), which stimulates the PI3K (phosphoinositide 3-kinase)/Akt pathway via p85alpha, the regulatory subunit of PI3K, in human skin fibroblasts. The aim of the present study was to elucidate the mechanism by which T3 activates PI3K, and to investigate the physiological role of this T3 action in neuronal cells. We found that T3 activates PI3K/Akt through Src. First, T3 rapidly induced the activation of Src and Akt in N2a cells expressing TRalpha1 (thyroid hormone receptor alpha1; N2aTRalpha), 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, T3 enhanced TRalpha1-p85alpha-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 T3 in N2aTRalpha cells. Moreover, it was also observed in primary cerebral cortical neurons that T3 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 T3 on neuronal cell survival, and provide new insights into the mechanism underlying this action, which involves Src activation and TRalpha1-p85alpha-Src complex formation.
Cao
Xia
X
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. caoxia@riem.nagoya-u.ac.jp
Kambe
Fukushi
F
Yamauchi
Masako
M
Seo
Hisao
H
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt