Dataset Information


Overexpression of 14-3-3? in cancer cells activates PI3K via binding the p85 regulatory subunit.

ABSTRACT: The ubiquitously expressed 14-3-3 proteins regulate many pathways involved in transformation. Previously, we found that 14-3-3? overexpression increased Akt phosphorylation in human mammary epithelial cells. Here, we investigated the clinical relevance and molecular mechanism of 14-3-3?-overexpression-mediated Akt phosphorylation, and its potential impact on breast cancer progression. We found that 14-3-3? overexpression was significantly (P=0.005) associated with increased Akt phosphorylation in human breast tumors. Additionally, 14-3-3? overexpression combined with strong Akt phosphorylation was significantly (P=0.01) associated with increased cancer recurrence in patients. In contrast, knockdown of 14-3-3? expression by small interfering RNA in cancer cell lines and tumor xenografts reduced Akt phosphorylation. Furthermore, 14-3-3? enhanced Akt phosphorylation through activation of phosphoinositide 3-kinase (PI3K). Mechanistically, 14-3-3? bound to the p85 regulatory subunit of PI3K and increased PI3K translocation to the cell membrane. A single 14-3-3-binding motif encompassing serine 83 on p85 is largely responsible for 14-3-3?-mediated p85 binding and PI3K/Akt activation. Mutation of serine 83 to alanine on p85 inhibited 14-3-3? binding to the p85 subunit of PI3K, reduced PI3K membrane localization and activation, impeded anchorage-independent growth and enhanced stress-induced apoptosis. These findings revealed a novel mechanism by which 14-3-3? overexpression activates PI3K, a key node in the mitogenic signaling network known to promote malignancies in many cell types.

PROVIDER: S-EPMC3193867 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC4442711 | BioStudies
| S-EPMC4119716 | BioStudies
| S-EPMC5312077 | BioStudies
| S-EPMC5801368 | BioStudies
| S-EPMC2747981 | BioStudies
| S-EPMC3546864 | BioStudies
| S-EPMC3319231 | BioStudies
| S-EPMC4004185 | BioStudies
| S-EPMC3637720 | BioStudies
| S-EPMC3117071 | BioStudies