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Akt1 contains a functional leucine-rich nuclear export sequence.
Motoyasu Saji1, Vasily Vasko, Faiza Kada
1The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA.
Biochemical and Biophysical Research Communications
|May 18, 2005
Summary
Nuclear Akt1, a protein involved in cancer invasion, has a newly identified nuclear export sequence (NES). Mutating this NES causes persistent nuclear localization and activation, enhancing cancer cell migration.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Nuclear Akt1 expression and activation are frequently observed in cancer invasion.
- The precise mechanisms linking Akt1's subcellular localization to invasion remain unclear.
Purpose of the Study:
- To investigate the mechanisms regulating Akt1 subcellular localization.
- To determine the functional significance of a potential nuclear export sequence (NES) in Akt1.
Main Methods:
- Bioinformatic analysis of Akt1 gene sequences to identify a potential NES.
- Leptomycin B treatment to assess nuclear Akt1 localization.
- Transient and stable transfection of wild-type and NES-mutated Akt1 (AKT/NES) in Akt1-/- fibroblasts.
- Assessment of CRM-1 interaction, subcellular localization, and cell migration.
Main Results:
- A conserved leucine-rich NES was identified in Akt1.
- Leptomycin B induced nuclear Akt1 localization.
- NES-mutated Akt1 (AKT/NES) exhibited reduced CRM-1 interaction and persistent nuclear localization.
- Stable expression of AKT/NES in Akt1-/- fibroblasts led to sustained nuclear Akt1 activation and enhanced in vitro cell migration.
Conclusions:
- Akt1 possesses a functional NES that mediates its nuclear export.
- Mutation of the Akt1 NES results in nuclear-predominant Akt1 activation.
- Nuclear-predominant Akt1 activation is sufficient to promote cancer cell migration.