Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70(S6K) cascade through phosphatidylinositol 3-kinase in human fibroblasts

We have demonstrated that T-3 increases the expression of ZAKI-4alpha, an endogenous calcineurin inhibitor. In this study we characterized a T-3-dependent signaling cascade leading to ZAKI-4alpha expression in human skin fibroblasts. We found that T-3-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 T-3. Indeed, T-3 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 T-3 induced Akt/PKB phosphorylation more rapidly than that of mTOR, and these T-3-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 T-3-induced PI3K activation and mTOR phosphorylation by a dominant negative TR (G345R) demonstrated the involvement of TR in this T-3 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 T-3 provides a new molecular mechanism for thyroid hormone action.