Phosphorylation of Thyroid Hormone Receptors by Protein Kinase A Regulates DNA Recognition by Specific Inhibition of Receptor Monomer Binding

Abstract

Thyroid hormone receptor (T3R) ␣-1 and its oncogenic derivative, the v-ERB A protein, are phosphorylated by cAMP-dependent protein kinase A. Although this phosphorylation appears to be necessary for the oncogenic properties of v-ERB A, the mechanism by which phosphorylation influences the functions of v-ERB A and of the normal T3R has not been established. The protein kinase A phosphorylation site in T3R␣-1 is within a domain that is known to contribute to the DNA recognition properties of these receptors. We therefore analyzed the effects of protein kinase A phosphorylation on DNA recognition by the normal T3R␣ and by the v-ERB A oncoprotein. We report here that phosphorylation of these receptor derivatives does not significantly alter the overall affinity of receptor dimers for DNA. However, phosphorylation does notably alter DNA recognition by preventing, or greatly inhibiting, the ability of these receptors to bind to DNA as protein monomers. These studies suggest that the phosphorylation of T3R␣-1 and v-ERB A by protein kinase A may provide a means of altering promoter recognition through a post-translational modification.

Genistein prevents thyroid hormone‐dependent tail regression of Rana catesbeiana tadpoles by targetting protein kinase C and thyroid hormone receptor α

“…Although the TRs are ligand-activated receptors, they can also be functionally regulated by phosphorylation (Lin et al, 1992;Bhat et al, 1994;Sugawara et al, 1994;Ting et al, 1997;Tzagarakis-Foster and Privalsky, 1998;Davis et al, 2000;Chen et al, 2003). Phosphorylation and dephosphorylation reactions are accomplished by multiple kinases and phosphatases.…”

Epidermal Growth Factor–Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor α

“…Phosphorylation of the HNF4 (NR2A1) DNA-binding domain enhances DNA binding (41), while phosphorylation of both NGF1-B (NR4A1) and T 3 Ra1 (NR1A1) in the DNA-binding domain by PKA inhibits DNA binding (42,43). PKC family members directly phosphorylate vitamin D receptor (VDR, NR1I1), retinoic acid receptor a (RARa, NR1B1), and COUP-TF1 (NR2F1) in the DNA-binding domain, with distinct transcriptional outcomes.…”

Roscovitine inhibits thyroid hormone‐induced tail regression of the frog tadpole and reveals a role for cyclin C/Cdk8 in the establishment of the metamorphic gene expression program

“…It is possible that other transcription factors may be targets of Cdk8 activity as its yeast homolog, Srb10, is capable of modulating transcription factor activity (Chi et al, 2001;Nelson et al, 2003). This could include TRs themselves because phosphorylation can lead to protein stabilization and signal potentiation as we have observed in anuran tail tissues (Ji et al, 2007) and others have observed in mammalian cells (Jones et al, 1994;Ting et al, 1997;Tzagarakis-Foster and Privalsky, 1998;KunoMurata et al, 2000;Chen et al, 2003).…”