title: Tyrosine phosphatases in the HER2-directed motility of ovarian cancer cells: Involvement of PTPN12, ERK5 and FAK.
abstract: BACKGROUND
  HER2 activation in tumours supports multiple signalling pathways, including those regulating invasion and metastasis. Among the involved genes, tyrosine and dual specificity phosphatases (PTPs and DSPs) may play a relevant, though not completely clear role.
  
  
  METHODS
  HER2 was silenced in ovarian SKOV-3 cells, a genome-wide expression analysis of PTPs and DSPs was performed, the effects on cell motility were analysed and compared with those of PTPN12-silencing, focusing on FAK.
  
  
  RESULTS
  HER2-silencing altered the expression of 4 PTPs and 6 DSPs; PTPN12 displayed also 3-4-fold protein increase. Conversely, PTPN12-silencing enhanced migration, suggesting that PTPN12 down-modulation by HER2 favours motility. HER2-silencing inactivated FAK, in quiescent and migrating cells, involving FAK dephosphorylation at Y397 and S910. Conversely, in PTPN12-silenced cells FAK activity was close to control, altogether suggesting that PTPN12 targets Y397. As regards to S910, cell-treatment with the MEK inhibitor UO126 and ERK5-silencing indicated its targeting by ERK5. Loss of pS910 and decreased ERK5 kinase activity in HER2-silenced cells confirmed their control by HER2.
  
  
  CONCLUSIONS
  The results indicate the contribution of PTPN12, targeting FAK Y397, and ERK5, targeting FAK S910, to the HER2-driven cell motility, thus depicting new aspects of the complex cross-talk between HER2 and the motility machinery.
authors.affiliation: Department of Experimental Pathology, via Roma 55, University of Pisa, 56126 Pisa, Italy. emma.villa@med.unipi.it
authors.forename: Emma
authors.initials: E
authors.lastname: Villa-Moruzzi
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D051417:Focal Adhesion Kinase 1; D020930:MAP Kinase Kinase Kinases; D048054:Mitogen-Activated Protein Kinase 7; D047428:Protein Kinase Inhibitors; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C496050:PTK2 protein, human; C481581:MAPK7 protein, human; C516738:PTPN12 protein, human