Cell
Volume 136, Issue 3, 6 February 2009, Pages 535-550
Journal home page for Cell

Article
PH Domain-Only Protein PHLDA3 Is a p53-Regulated Repressor of Akt

https://doi.org/10.1016/j.cell.2008.12.002Get rights and content
Under an Elsevier user license
open archive

Summary

p53 and Akt are critical players regulating tumorigenesis with opposite effects: whereas p53 transactivates target genes to exert its function as a tumor suppressor, Akt phosphorylates its substrates and transduces downstream survival signals. In addition, p53 and Akt negatively regulate each other to balance survival and death signals within a cell. We now identify PHLDA3 as a p53 target gene that encodes a PH domain-only protein. We find that PHLDA3 competes with the PH domain of Akt for binding of membrane lipids, thereby inhibiting Akt translocation to the cellular membrane and activation. Ablation of endogenous PHLDA3 results in enhanced Akt activity and decrease of p53-dependent apoptosis. We also demonstrate the suppression of anchorage-independent cell growth by PHLDA3. Loss of the PHLDA3 genomic locus was frequently observed in primary lung cancers, suggesting a role of PHLDA3 in tumor suppression. Our results reveal a new mode of coordination between the p53 and Akt pathways.

HUMDISEASE
SIGNALING

Cited by (0)

11

These authors contributed equally to the work