Functional analysis of a novel signaling cascade activated by thyroid hormone: Role of PI3 kinase→PKB→mTOR→ZAKI-4αactivation by thyroid hormone

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Thyroid hormone (TH) is essential for normal development, growth and metabolism. Its effects are mediated through triiodothyronine (T_3), which acts as a ligand for the TH receptors (TRs). In the classical model of genes positively regulated by TH, the TR first binds as a heterodimer or homodimer on TH response elements (TRE) located in the promoter regions of target genes, where it interacts with corepressors. Upon ligand binding, the TR homodimers are dissociated in favor of heterodimer formation with the retinoid-X receptor (RXR), resulting in release of the corepressors and recruitment of coactivators. This new complex attracts a large number of proteins which engage the RNA polymerase II in the transcription of the targeted gene. In addition to the classical, "nuclear" mode of TH action, we demonstrated that TH also activates PI3K-Akt signaling pathway rapidly through a non-genomic mechanism. It was found that 1) TH treatment induced sequential phosphorylation and activation of th … More e serine/threonine kinase Akt, the mammalian target of rapamycin (mTOR) and its substrate p70^<S6K> and 2) phosphorylation of these proteins was abrogated by both PI3K inhibitors, LY294002 and wortmannin, and by a dominant negative regulatory subunit of PI3K (p85a). This TH action is very rapid and independent of protein synthesis, suggesting that it does not involve the typical nuclear action of TR. It is of note that this rapid TH action was abrogated by the introduction of a dominant negative TRP (TRG345R) into the cells expressing the wild type TRβ, indicating the participation of TRβ. It was demonstrated that TRβ directly interacts with the regulatory subunit of PI3K, p85a in human skin fibroblasts. The interaction is independent of ligand binding, while PI3K can be activated only in the presence of TH. We and others identified several genes under the control of this action, including ZAKI-4a, hypoxia-inducible factor-la, glucose transporter 1, phosphofructokinase, and the monocarboxylate transporter 4. ZAKI-4 gene was originally identified by us as a thyroid hormone (TH) responsive gene which locates on human chromosome 6. We later found that three transcripts, a, β1 and β2, were generated by the single ZAKI-4 gene through differential splicing. The β1 and β2 isoforms encode the same protein product ZAKI-4β, which shares the common carboxyl terminal region with ZAKI-4a. Both ZAKI-4a and β belong to a family of small structurally related proteins which bind to, and down-regulate the activity of calcineurin (protein phosphatase 2B). It was demonstrated in human and rodents that the expression of only a isoform is upregulated. by TH. Since it is known that calcineurin is involved in neuronal plasticity, TH may play the role in neuronal plasticity through regulating calcineurin activity. Less