Abstract
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 Gab1 PH domain decoy.
Conclusion:
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Breast Neoplasms / enzymology*
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Breast Neoplasms / genetics
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COS Cells
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Chlorocebus aethiops
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Enzyme Activation / physiology
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Epidermal Growth Factor / antagonists & inhibitors
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / physiology
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Humans
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Matrix Metalloproteinase 9 / biosynthesis
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Matrix Metalloproteinase Inhibitors
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / metabolism
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PTEN Phosphohydrolase
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Phosphoproteins / genetics
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Phosphoproteins / physiology*
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Phosphoric Monoester Hydrolases / antagonists & inhibitors*
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Phosphoric Monoester Hydrolases / physiology
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Protein Serine-Threonine Kinases*
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction / physiology
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / antagonists & inhibitors*
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Tumor Suppressor Proteins / physiology
Substances
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Adaptor Proteins, Signal Transducing
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GAB1 protein, human
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Matrix Metalloproteinase Inhibitors
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Phosphoproteins
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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Epidermal Growth Factor
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ErbB Receptors
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Matrix Metalloproteinase 9