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Development and Application of Rapamycin-regulated Tyrosine Phosphatases
Published on: September 6, 2024
Rheb and mTOR regulate neuronal polarity through Rap1B.
Ying-Hua Li1, Hendrikje Werner, Andreas W Püschel
1Abteilung Molekularbiologie, Institut für Allgemeine Zoologie und Genetik, Westfälische Wilhelms-Universität Münster, Schlossplatz 5, D-48149 Münster, Germany.
The Journal of Biological Chemistry
|October 10, 2008
Summary
Phosphoinositide 3-kinase (PI3K) regulates neuronal polarity via the Rheb-mTOR pathway, controlling axon formation by modulating Rap1B levels. This pathway counteracts Smurf2-mediated Rap1B degradation.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Neuronal polarity, characterized by a single axon and multiple dendrites, is crucial for proper brain function.
- The phosphoinositide 3-kinase (PI3K) pathway and the GTPase Rap1B are known to be involved in this process.
Purpose of the Study:
- To elucidate the molecular mechanisms by which PI3K regulates axon specification and elongation.
- To identify the downstream targets and pathways mediating PI3K's role in neuronal polarity.
Main Methods:
- Overexpression and RNA interference (RNAi) of Rheb (Ras homolog enriched in brain).
- Inhibition of mammalian target of rapamycin (mTOR) and use of mTOR-insensitive 4E-binding protein 1 (4E-BP1) mutants.
- Analysis of Rap1B protein levels and the role of the ubiquitin E3 ligase Smurf2.
Main Results:
- PI3K regulates axon specification and elongation through Rheb and its downstream target mTOR.
- Overexpression of Rheb led to multiple axons, while its suppression blocked axon formation.
- mTOR inhibition and expression of mTOR-insensitive 4E-BP1 mutants suppressed axon formation.
- PI3K or mTOR inhibition reduced Rap1B levels, which are degraded by Smurf2.
- Suppression of Smurf2 could rescue the effects of Rheb loss.
Conclusions:
- The mTOR pathway is essential for neuronal polarity by counteracting Smurf2-mediated degradation of Rap1B.
- Rheb acts upstream of mTOR, and both are critical for regulating Rap1B levels during axon development.
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