title: Doubles game: Src-Stat3 versus p53-PTEN in cellular migration and invasion.
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.
authors: Department of Biochemistry, Queen's University, Kingston, ON, Canada.
authors: Utpal K
authors: UK
authors: Mukhopadhyay
authors: Patrick
authors: P
authors: Mooney
authors: Lilly
authors: L
authors: Jia
authors: Robert
authors: R
authors: Eves
authors: Leda
authors: L
authors: Raptis
authors: Alan S
authors: AS
authors: Mak
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000502:physiology; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D019061:src-Family Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D002148:Calmodulin-Binding Proteins; D017931:DNA Primers; D061965:Matrix Metalloproteinase Inhibitors; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D019061:src-Family Kinases; D051059:PTEN Phosphohydrolase; D053506:Matrix Metalloproteinase 10; D020781:Matrix Metalloproteinase 1