Related Experiment Video

Updated: Jan 4, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

9.0K

Glycogen synthase kinase-3β suppresses the expression of protein phosphatase methylesterase-1 through β-catenin

Nana Jin1, Ruirui Shi1, Yanli Jiang1

  • 1Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.

Aging
|November 13, 2019
PubMed

Insights

Glycogen synthase kinase-3β (GSK-3β) regulates Protein phosphatase methylesterase-1 (PME-1) expression by phosphorylating β-catenin. This mechanism controls PP2A methylation and tau phosphatase activity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Protein phosphatase 2A (PP2A) is a key tau phosphatase, and its activity is modulated by the methylation of its catalytic subunit (PP2Ac) at Leu309.
  • Protein phosphatase methylesterase-1 (PME-1) is responsible for PP2Ac demethylation, thereby reducing PP2A activity.
  • Previous research indicated that glycogen synthase kinase-3β (GSK-3β) suppresses PME-1 expression, but the mechanism remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which GSK-3β suppresses PME-1 expression.
  • To investigate the role of β-catenin and specific promoter elements in regulating PME-1 expression.
  • To determine how the PI3K-AKT pathway influences PME-1 expression via GSK-3β.

Main Methods:

  • Promoter analysis of the human PME-1 gene to identify cis-regulatory elements.
  • Investigation of the interaction between β-catenin, GSK-3β, and the PME-1 promoter.
  • Pharmacological manipulation of GSK-3β activity using the PI3K-AKT pathway in neuronal cells and mouse brain models.

Main Results:

  • The human PME-1 promoter contains two lymphoid enhancer binding factor-1/T-cell factor (LEF1/TCF) cis-elements where β-catenin acts as a co-activator to promote PME-1 expression.
  • GSK-3β phosphorylates β-catenin, thereby inhibiting its co-activator function and suppressing PME-1 expression.
  • Modulation of GSK-3β activity through the PI3K-AKT pathway directly affected PME-1 expression in cultured neurons, SH-SY5Y cells, and the mouse brain.

Conclusions:

  • GSK-3β negatively regulates PME-1 expression by phosphorylating β-catenin, which interferes with its ability to promote PME-1 transcription.
  • This GSK-3β-β-catenin pathway is a critical determinant of PME-1 levels and, consequently, PP2Ac methylation status.
  • The findings reveal a novel regulatory axis controlling tau phosphatase activity with implications for neurodegenerative diseases associated with tau pathology.
Keywords:
GSK-3βLEF1/TCF cis-elementPME-1methylationβ-catenin

More Related Videos

Reconstitution Of β-catenin Degradation In Xenopus Egg Extract09:41

Reconstitution Of β-catenin Degradation In Xenopus Egg Extract

Published on: June 17, 2014

12.4K
Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway07:15

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway

Published on: August 23, 2024

821

Related Concept Videos

Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
16.1K
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...
5.2K
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...
10.3K
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...
16.8K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
8.1K
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...
11.7K