Simultaneous suppression of erk and Akt/PKB activation by a Gab1 pleckstrin homology (PH) domain decoy

Background: Gab1 is a pleckstrin homology (PH) domain containing docking protein that mediates EGF-induced Erk and Akt/PKB activation. Using a decoy strategy, we explored the Gab1 PH domain as a potential target for simultaneous inhibition of Erk and Akt/PKB activation. Materials and Methods: MDA-MB-468 and SK-BR-3 derived cell lines were established for doxycycline-inducible expression of a Gab1 PH domain decoy. Erk and Akt activation, matrix metalloprotease-9 (MMP-9) secretion and cell motility were analyzed. Results: Expression of the Gab1 PH domain decoy in these cells suppressed EGF-induced Erk2 and Akt/PKB activation,, MMP-9 secretion and cell migration. The constitutively active Akt/PKB in the PTEN-negative MDA-MB-468 cells was also suppressed by the Gab1PH domain decoy. Conclusion: These results illustrate that the Gab1PH domain is a potential target for antagonizing ErbB activation and PTEN inactivation, and for suppression of ErbB-induced metastatic activities in breast cancer cells.