Implication of the MAGI-1b/PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness.
We recently established the critical role of the lipid phosphatase activity of the PTEN tumor suppressor in stabilizing cell-cell contacts and suppressing invasiveness. To delineate the effector systems involved, we investigated the interaction of PTEN with E-cadherin junctional complexes in kidney and colonic epithelial cell lines. PTEN and the p85 regulatory subunit of phosphatidylinositol 3-OH kinase (PI3K) co-immunoprecipitated with E-cadherin and catenins. By using a yeast two-hybrid assay, we demonstrated that PTEN interacted indirectly with beta-catenin by binding the scaffolding protein MAGI-1b. This model was corroborated in various ways in mammalian cells. Ectopic expression of MAGI-1b potentiated the interaction of PTEN with junctional complexes, promoted E-cadherin-dependent cell-cell aggregation, and reverted the Src-induced invasiveness of kidney MDCKts-src cells. In this model, MAGI-1b slightly decreased the activity of AKT, a downstream effector of PI3K. By using dominant-negative and constitutively active AKT expression vectors, we demonstrated that this kinase was included in the pathways involved in Src-induced destabilization of junctional complexes and was necessary and sufficient to trigger invasiveness. We propose that the recruitment of PTEN at adherens junctions by MAGI-1b and the local down-regulation of phosphatidylinositol-3,4,5-trisphosphate pools and downstream effector systems at the site of cell-cell contacts are focal points for restraining both disruption of junctional complexes and induction of tumor cell invasion.
Kotelevets
Larissa
L
INSERM U410, Faculté de Médecine Bichat, Paris, France.
van Hengel
Jolanda
J
Bruyneel
Erik
E
Mareel
Marc
M
van Roy
Frans
F
Chastre
Eric
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051943:Antennapedia Homeodomain Protein; D018938:Caco-2 Cells / Q000737:chemistry / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics; D015815:Cell Adhesion Molecules; D002460:Cell Line; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D016391:Genes, src; D051528:Guanylate Kinases; D019073:HT29 Cells / Q000737:chemistry / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry; D051059:PTEN Phosphohydrolase; D010711:Phosphatidate Phosphatase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D051178:alpha Catenin
D048868:Adaptor Proteins, Signal Transducing; D051943:Antennapedia Homeodomain Protein; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051528:Guanylate Kinases; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D010711:Phosphatidate Phosphatase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051178:alpha Catenin; C495273:CTNNA1 protein, human; C494918:AKT1 protein, human; C493280:Magi1 protein, mouse; C112948:lipid phosphate phosphatase; C494929:PTEN protein, human