Related Experiment Video

Updated: Aug 13, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor

Fumihiko Furuya1, John A Hanover, Sheue-yann Cheng

  • 1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-4264, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 1, 2006
PubMed

Insights

A mutant thyroid hormone receptor (TRbetaPV) activates phosphatidylinositol 3-kinase (PI3K) signaling by binding to p85alpha. This interaction contributes to thyroid cancer development by affecting PI3K downstream pathways in both nuclear and cytoplasmic compartments.

Area of Science:

  • Molecular Biology
  • Oncology
  • Endocrinology

Background:

  • The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is frequently activated in human cancers.
  • A mouse model with a mutant thyroid hormone beta receptor (TRbetaPV) spontaneously develops thyroid cancer and metastasis, mimicking human follicular thyroid carcinoma.
  • Previous studies indicated AKT activation in this mouse model's thyroid tumors and metastatic lesions.

Purpose of the Study:

  • To investigate the interaction between the TRbetaPV mutant and the PI3K pathway in thyroid tumors.
  • To elucidate the mechanism by which the TRbetaPV mutant influences PI3K activity and downstream signaling.
  • To identify the specific cellular compartments involved in these molecular events.

Main Methods:

  • GST pull-down assays to identify protein interaction sites.
  • Confocal fluorescence microscopy to visualize protein colocalization.
  • Biochemical analysis to assess pathway activation in different cellular compartments.

Main Results:

  • The TRbetaPV mutant exhibited increased binding to the PI3K regulatory subunit p85alpha compared to wild-type TRbeta1, leading to enhanced PI3K kinase activity.
  • The ligand-binding domain of TR was identified as the interaction site with p85alpha.
  • p85alpha colocalized with TRbeta1 or PV in both nuclear and cytoplasmic compartments of cultured tumor cells.
  • PI3K-AKT-mTOR-p70S6K pathway activation occurred in both cytoplasmic and nuclear compartments.
  • PI3K-ILK-MMP2 pathway activation was primarily detected in extranuclear compartments.

Conclusions:

  • The TRbetaPV mutant activates PI3K signaling through direct protein-protein interaction with p85alpha.
  • This interaction affects PI3K downstream signaling in both nuclear and extranuclear cellular compartments.
  • The findings reveal a novel mechanism by which a mutant TR contributes to thyroid carcinogenesis via PI3K activation.

More Related Videos

In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse04:14

In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse

Published on: October 6, 2023

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors08:45

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors

Published on: July 17, 2020

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...