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Molecular Endocrinology, doi:10.1210/me.2004-0093
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Molecular Endocrinology 19 (1): 102-112
Copyright © 2005 by The Endocrine Society

Thyroid Hormone Induces Rapid Activation of Akt/Protein Kinase B-Mammalian Target of Rapamycin-p70S6K Cascade through Phosphatidylinositol 3-Kinase in Human Fibroblasts

Xia Cao, Fukushi Kambe, Lars C. Moeller, Samuel Refetoff and Hisao Seo

Research Institute of Environmental Medicine (X.C., F.K., H.S.), Nagoya University, Nagoya 464-8601, Japan; and Departments of Medicine (L.C.M., S.R.), Pediatrics (S.R.), and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Hisao Seo, Research Institute of Environmental Medicine, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: hseo{at}riem.nagoya-u.ac.jp.

We have demonstrated that T3 increases the expression of ZAKI-4{alpha}, an endogenous calcineurin inhibitor. In this study we characterized a T3-dependent signaling cascade leading to ZAKI-4{alpha} expression in human skin fibroblasts. We found that T3-dependent increase in ZAKI-4{alpha} 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 p70S6K, 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 ({Delta}p85{alpha}). Furthermore, the association between thyroid hormone receptor ß1 (TRß1) and PI3K-regulatory subunit p85{alpha}, 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-p70S6K cascade by T3 provides a new molecular mechanism for thyroid hormone action.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ
Ligands:   Thyroid hormone



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