Nongenomic Thyroid Hormone Signaling Occurs Through a Plasma Membrane–Localized Receptor

Abstract

Thyroid hormone (TH) is essential for vertebrate development and the homeostasis of most adult tissues, including bone. TH stimulates target gene expression through the nuclear thyroid receptors TRα and TRβ; however, TH also has rapid, transcription-independent (nongenomic) effects. We found a previously uncharacterized plasma membrane-bound receptor that was necessary and sufficient for nongenomic TH signaling in several cell types. We determined that this receptor is generated by translation initiation from an internal methionine of TRα, which produces a transcriptionally incompetent protein that is palmitoylated and associates with caveolin-containing plasma membrane domains. TH signaling through this receptor stimulated a pro-proliferative and pro-survival program by increasing the intracellular concentrations of calcium, nitric oxide (NO), and cyclic guanosine monophosphate (cGMP), which led to the sequential activation of protein kinase G II (PKGII), the tyrosine kinase Src, and extracellular signal-regulated kinase (ERK) and Akt signaling. Hypothyroid mice exhibited a cGMP-deficient state with impaired bone formation and increased apoptosis of osteocytes, which was rescued by a direct stimulator of guanylate cyclase. Our results link nongenomic TH signaling to a previously uncharacterized membrane-bound receptor, and identify NO synthase, guanylate cyclase, and PKGII as TH effectors that activate kinase cascades to regulate cell survival and proliferation.

Hepatic FOXO1 Target Genes Are Co-regulated by Thyroid Hormone via RICTOR Protein Deacetylation and MTORC2-AKT Protein Inhibition

“…2H). Recently, Kalyanaraman et al (51) have also shown similar results in primary osteoblasts in which they showed that T 3 rapidly stimulated the phosphorylation of Src, ERK1/2, and Akt within 2-30 min and then returned to its basal amounts after 30 min. The reduction of AKT phosphorylation by TH led to decreased FOXO1 phosphorylation and increased nuclear localization in HepG2 cells (Figs.…”

Thyroid hormone regulated genes in cerebral cortex development

“…In addition, there are several truncated proteins lacking either the DNAbinding domain or a functional T 3 binding domain. A TRα protein lacking the DNAbinding domain is attached to the plasma cell membrane and mediates the actions of T 3 on PI3K signaling (Kalyanaraman et al 2014). …”

Role of Pleiotropic Properties of Peroxisome Proliferator‐Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection

“…For example, nongenomic actions of thyroid hormone are initiated at a specific receptor on a cell surface protein (integrin avb3) [132] or at truncated isoforms of nuclear receptor TRa at the plasma membrane or in cytoplasm [133,134]. The hormone also acts nongenomically on mitochondria via another TR isoform [135].…”