Thyroid Hormone Induces Rapid Activation of Akt/Protein Kinase B-Mammalian Target of Rapamycin-p70S6KCascade through Phosphatidylinositol 3-Kinase in Human Fibroblasts

• DOI: 10.1210/me.2004-0093
• Publication Date: 2004-09-24T00:15:57Z
• Authors: Xia Cao; Fukushi Kambe; Lars C. Moeller; Samuel Refetoff; Hisao Seo
• Keywords: Sirolimus; 0303 health sciences; Active Transport, Cell Nucleus; Muscle Proteins; Ribosomal Protein S6 Kinases, 70-kDa; Fibroblasts; Protein Serine-Threonine Kinases; Ligands; 3. Good health; Enzyme Activation; Phosphatidylinositol 3-Kinases; Phosphoserine; Protein Subunits; 03 medical and health sciences; Gene Expression Regulation; Proto-Oncogene Proteins; Humans; Cycloheximide; Protein Kinases; Proto-Oncogene Proteins c-akt; Cells, Cultured; Protein Binding; Signal Transduction

We have demonstrated that T3 increases the expression of ZAKI-4alpha, an endogenous calcineurin inhibitor. In this study we characterized a T3-dependent signaling cascade leading to ZAKI-4alpha expression in human skin fibroblasts. We found that T3-dependent increase in ZAKI-4alpha was greatly attenuated by rapamycin, a specific inhibitor of a protein kinase, mammalian target of rapamycin (mTOR), suggesting the requirement of mTOR activation by T3. Indeed, T3 activated mTOR rapidly through S2448 phosphorylation, leading to the phosphorylation of p70(S6K), a substrate of mTOR. This mTOR activation is mediated through phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) signaling cascade because T3 induced Akt/PKB phosphorylation more rapidly than that of mTOR, and these T3-dependent phosphorylations were blocked by both PI3K inhibitors and by expression of a dominant negative PI3K (Deltap85alpha). Furthermore, the association between thyroid hormone receptor beta1 (TRbeta1) and PI3K-regulatory subunit p85alpha, and the inhibition of T3-induced PI3K activation and mTOR phosphorylation by a dominant negative TR (G345R) demonstrated the involvement of TR in this T3 action. The liganded TR induces the activation of PI3K and Akt/PKB, leading to the nuclear translocation of the latter, which subsequently phosphorylates nuclear mTOR. The rapid activation of PI3K-Akt/PKB-mTOR-p70(S6K) cascade by T3 provides a new molecular mechanism for thyroid hormone action.