Related Experiment Video

Updated: Jun 19, 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

Phosphorylation of neuronal survival factor MEF2D by glycogen synthase kinase 3beta in neuronal apoptosis

Xuemin Wang1, Hua She, Zixu Mao

  • 1Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

The Journal of Biological Chemistry
|October 6, 2009
PubMed

Insights

Glycogen synthase kinase 3beta (GSK3beta) directly phosphorylates and inhibits the survival factor MEF2D, leading to neurotoxicity. This reveals a new mechanism linking GSK3beta activation to neuronal death pathways.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Glycogen synthase kinase 3beta (GSK3beta) is implicated in neuronal death and Alzheimer's disease pathogenesis.
  • The precise molecular mechanisms of GSK3beta-mediated neurotoxicity are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which GSK3beta contributes to neurotoxicity.
  • To identify novel downstream effectors of GSK3beta involved in neuronal survival.

Main Methods:

  • Investigated the interaction between GSK3beta and myocyte enhancer factor 2D (MEF2D) using in vitro and in vivo models.
  • Assessed the effect of GSK3beta phosphorylation on MEF2D transcriptional activity.
  • Utilized neuronal activity deprivation and GSK3beta activation in cerebellar granule neurons.
  • Employed overexpression of a GSK3beta-resistant MEF2D mutant.

Main Results:

  • GSK3beta directly phosphorylates the transcription factor MEF2D at three residues within its transactivation domain.
  • This phosphorylation inhibits MEF2D's transcriptional activity, contributing to neurotoxicity.
  • GSK3beta activation, induced by neuronal activity withdrawal, impairs MEF2D function and promotes neuronal death.
  • Overexpressing a GSK3beta-resistant MEF2D mutant protected neurons from toxicity.

Conclusions:

  • Identified MEF2D as a novel downstream target of GSK3beta, linking GSK3beta to neuronal survival pathways.
  • Demonstrated that GSK3beta-mediated inhibition of MEF2D contributes to neurotoxicity.
  • Provides a molecular link between GSK3beta activation and impaired neuronal survival machinery.

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...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...