Tyrosine Phosphatases in the HER2-directed Motility of Ovarian Cancer Cells: Involvement of PTPN12, ERK5 and FAK

Anal Cell Pathol (Amst). 2011;34(3):101-12. doi: 10.3233/ACP-2011-0008.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Enzyme Activation
  • Female
  • Focal Adhesion Kinase 1 / metabolism*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism*
  • RNA Interference
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction
  • Time Factors

Substances

  • Protein Kinase Inhibitors
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase Kinases
  • PTPN12 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12