Abstract
We have recently shown that Src induces the formation of podosomes and cell invasion by suppressing endogenous p53, while enhanced p53 strongly represses the Src-induced invasive phenotype. However, the mechanism by which Src and p53 play antagonistic roles in cell invasion is unknown. Here we show that the Stat3 oncogene is a required downstream effector of Src in inducing podosome structures and related invasive phenotypes. Stat3 promotes Src phenotypes through the suppression of p53 and the p53-inducible protein caldesmon, a known podosome antagonist. In contrast, enhanced p53 attenuates Stat3 function and Src-induced podosome formation by upregulating the tumor suppressor PTEN. PTEN, through the inactivation of Src/Stat3 function, also stabilizes the podosome-antagonizing p53/caldesmon axis, thereby further enhancing the anti-invasive potential of the cell. Furthermore, the protein phosphatase activity of PTEN plays a major role in the negative regulation of the Src/Stat3 pathway and represses podosome formation. Our data suggest that cellular invasiveness is dependent on the balance between two opposing forces: the proinvasive oncogenes Src-Stat3 and the anti-invasive tumor suppressors p53-PTEN.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Base Sequence
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Calmodulin-Binding Proteins / antagonists & inhibitors
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Calmodulin-Binding Proteins / genetics
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Calmodulin-Binding Proteins / physiology
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Cell Line
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Cell Movement / genetics
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Cell Movement / physiology*
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DNA Primers / genetics
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Gene Knockdown Techniques
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Matrix Metalloproteinase 1 / genetics
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Matrix Metalloproteinase 1 / physiology
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Matrix Metalloproteinase 10 / genetics
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Matrix Metalloproteinase 10 / physiology
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Matrix Metalloproteinase Inhibitors
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Mice
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Models, Biological
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Mutant Proteins / genetics
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Mutant Proteins / physiology
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Myocytes, Smooth Muscle / physiology
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / physiopathology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / physiology*
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Phenotype
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RNA, Small Interfering / genetics
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Rats
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / physiology*
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / physiology*
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src-Family Kinases / genetics
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src-Family Kinases / physiology*
Substances
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Calmodulin-Binding Proteins
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DNA Primers
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Matrix Metalloproteinase Inhibitors
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Mutant Proteins
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RNA, Small Interfering
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Recombinant Proteins
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STAT3 Transcription Factor
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Tumor Suppressor Protein p53
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src-Family Kinases
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PTEN Phosphohydrolase
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Matrix Metalloproteinase 10
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Matrix Metalloproteinase 1