Related Experiment Video
Updated: Jul 16, 2026
07:55
Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
Published on: October 17, 2015
GSK3beta activity modifies the localization and function of presenilin 1
Kengo Uemura1, Akira Kuzuya, Yoshiharu Shimozono
1Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto, Japan.
The Journal of Biological Chemistry
|March 29, 2007
Summary
Presenilin 1 (PS1) localization at the cell surface is regulated by N-cadherin interactions and phosphorylation. Glycogen synthase kinase 3beta-mediated PS1 phosphorylation impacts Alzheimer
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Presenilin 1 (PS1) is implicated in familial Alzheimer disease and primarily localized to the endoplasmic reticulum and Golgi.
- Endogenous PS1 is also biologically active at the plasma membrane, interacting with N-cadherin and beta-catenin.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing Presenilin 1/gamma-secretase's subcellular distribution and substrate cleavage.
- To investigate the role of N-cadherin-based cell-cell contact and glycogen synthase kinase 3beta (GSK3beta) phosphorylation in PS1 regulation.
Main Methods:
- Investigated cell-surface expression of PS1/gamma-secretase in response to N-cadherin-mediated cell-cell contact.
- Analyzed physical interactions between PS1, N-cadherin, and beta-catenin.
- Examined the effect of GSK3beta-mediated phosphorylation of PS1 on its binding affinity and downstream signaling pathways.
- Assessed the impact of PS1 phosphorylation on epsilon-cleavage of N-cadherin and APP.
Main Results:
- Cell-surface expression of PS1/gamma-secretase is enhanced by N-cadherin-based cell-cell contact through physical interaction with N-cadherin/beta-catenin.
- GSK3beta-mediated phosphorylation of PS1 reduces its binding to N-cadherin, down-regulating cell-surface expression.
- Reduced PS1.N-cadherin.beta-catenin complex formation impairs phosphatidylinositol 3-kinase/Akt cell survival signaling.
- PS1 phosphorylation hinders N-cadherin epsilon-cleavage but does not affect APP epsilon-cleavage.
Conclusions:
- This study clarifies the regulatory mechanism of PS1/gamma-secretase localization and differential substrate cleavage.
- GSK3beta-mediated phosphorylation of PS1 is a key regulator of its cell-surface expression and interaction with N-cadherin/beta-catenin.
- Dysregulated GSK3beta activity can reduce neuronal viability and synaptic plasticity, implicating it in Alzheimer disease pathophysiology.
Related Concept Videos
01:12GPCR Desensitization
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
01:45Regulation of Nuclear Protein Sorting
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
01:20The 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...
01:22Amplifying 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...