Akt1 contains a functional leucine-rich nuclear export sequence.
Nuclear Akt1 expression and Akt activation are common in cancer invasion. However, the mechanisms for this association and its causal role in invasion are uncertain. In an effort to identify potential mechanisms for regulating Akt subcellular localization, we analyzed the Akt gene sequences and identified a highly conserved leucine-rich potential nuclear export sequence (NES). Initial experiments demonstrated that leptomycin B induced nuclear Akt1 localization. Transient expression experiments demonstrated that, in comparison to wild-type Akt1, NES-mutated (AKT/NES) Akt1 has reduced interactions with CRM-1 and persistent nuclear localization. Subsequent stable transfection experiments in Akt1-/- fibroblasts confirmed that expression of AKT/NES resulted in persistent nuclear localization and activation1. Finally, stable expression of AKT/NES in Akt1-/- fibroblasts was sufficient to enhance cell migration in vitro. Thus, Akt1 contains a functional NES and mutation of the NES results in nuclear-predominant Akt1 activation that is sufficient to induce migration.
Saji
Motoyasu
M
The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA.
Vasko
Vasily
V
Kada
Faiza
F
Allbritton
Elena Hardy
EH
Burman
Kenneth D
KD
Ringel
Matthew D
MD
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D002460:Cell Line; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007930:Leucine / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013329:Structure-Activity Relationship; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology
D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D007930:Leucine