Hepatocyte growth factor differently influences Met-E-cadherin phosphorylation and downstream signaling pathway in two models of breast cells.
E-cadherins are implicated in cell adhesion, and also in cell signaling by associating with tyrosine kinase-receptors such as Met, the hepatocyte growth factor (HGF) receptor. Using two different cellular models, i.e. MCF-7 (breast carcinoma) and MCF-10 (immortalized mammary) cells, we studied the possible mechanism(s) by which E-cadherins modulate the signaling pathways downstream of Met, leading to beta-catenin-TCF transcriptional activity. In MCF-7, but not in MCF-10 cells, E-cadherins were remarkably associated with Met. Moreover, in MCF-7 cells both co-immunoprecipitation with anti-Met antibody and co-localization were increased by 30-min HGF treatment, which caused E-cadherin tyrosine phosphorylation. Also beta-catenin in the co-immunoprecipitate was phosphorylated by HGF, probably favoring TCF activation. Consistently, after HGF treatment, beta-catenin redistributed earlier in MCF-7 than in MCF-10 cells, with nuclear accumulation and activation of TOPFLASH gene reporter. Our results indicate a functional role of Met-E-cadherin interaction in MCF-7 cells through the amplification of the signaling downstream of HGF-Met triggering that involved c-Src and phosphoinositide-3-kinase activities.
Matteucci
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Institute of General Pathology, University of Milan, via Luigi Mangiagalli 31, 20133 Milan, Italy.
Ridolfi
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Desiderio
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MA
D001943:Breast Neoplasms / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000502:physiology; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D051820:TCF Transcription Factors; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src)