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.


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 Gab1 PH domain decoy.


CONCLUSIONS
These results illustrate that the Gab1 PH domain is a potential target for antagonizing ErbB activation and PTEN inactivation, and for suppression of ErbB-induced metastatic activities in breast cancer cells.
Ren
Yuan
Y
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Wu
Jie
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000502:physiology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D061965:Matrix Metalloproteinase Inhibitors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020780:Matrix Metalloproteinase 9