| MAGI-1 interacts with the PTEN tumor suppressor and the key signaling molecule, beta-catenin, through its PDZ2 and PDZ5 domains, respectively. Expression analysis revealed an inverse correlation between MAGI-1 expression and the levels of free beta-catenin in breast tumor cells. By luciferase-based transcriptional reporter assays, MAGI-1 suppressed beta-catenin-mediated TCF/LEF transcription activity in a dose-dependent manner. This inhibitory effect was further enhanced by the co-expression of PTEN. By using a panel of MAGI-1 PDZ-deletion mutants, we have validated the involvement of both PDZ2 and PDZ5 domains in suppressing beta-catenin function. To study the physiological functions of MAGI-1, a knockout mouse strain was generated; clinical manifestation of proteinuria was detected. Indeed, electron microscopy studies showed striking effacement of the podocytes in kidneys from MAGI-1 deficient mice. Our data provides evidence for MAGI-1 importance in maintaining junctional integrity of podocytes as well as cooperating with PTEN in suppressing the transcriptional activity of beta-catenin. |
