Pleckstrin‐2‐promoted PPM1B degradation plays an important role in transforming growth factor‐β‐induced breast cancer cell invasion and metastasis

Abstract Transforming growth factor‐β (TGF‐β) is known to promote breast cancer cell migration, invasion, and dissemination; however, the underlying molecular mechanisms are not yet well characterized. Here, we report that TGF‐β induces pleckstrin‐2 (PLEK2) expression by Smad3 and signal transducer and activator of transcription 3 (STAT3) activating PLEK2 promoter activity. Higher PLEK2 expression is associated with poor prognosis in breast cancer patients. Overexpression and knockout experiments in MDA‐MB‐231 and MCF‐7 breast cancer cells revealed that PLEK2 promotes cell migration, invasion, and dissemination in 2D and 3D cell culture. Moreover, PLEK2 promotes metastasis of breast cancer cells in vivo. Pleckstrin‐2 localizes to the cell membrane and cell protrusions following TGF‐β treatment. Furthermore, inhibition of PI3K phosphorylation abolishes TGF‐β‐ and PLEK2‐induced cell invasion. The carboxyl‐terminal PH domain of PLEK2 is critical for TGF‐β‐ and PLEK2‐induced Akt activation and plays an important role in cell invasion. Pleckstrin‐2 interacts with PPM1B and promotes its ubiquitin‐dependent degradation. The PLEK2‐PPM1B axis utilizes nuclear factor‐κB signaling to promote cell migration and invasion. Our data implicate the TGF‐β‐STAT3/Smad3‐PLEK2‐PPM1B signaling cascade in TGF‐β‐induced breast cancer cell migration and invasion. These findings suggest that PLEK2/PPM1B could represent novel targets for the intervention of breast cancer metastasis.