Merlin-deficient human tumors show loss of contact inhibition and activation of Wnt/β-catenin signaling linked to the PDGFR/Src and Rac/PAK pathways.

Lu Zhou, Emanuela Ercolano, Sylwia Ammoun, MC Schmid, Magdalena A. Barczyk, Clemens Oliver Hanemann

Research output: Contribution to journalArticlepeer-review

Abstract

Neurofibromatosis type 2 (NF2) is an inherited predisposition cancer syndrome characterized by the development of multiple benign tumors in the nervous system including schwannomas, meningiomas, and ependymomas. Using a disease model comprising primary human schwannoma cells, we previously demonstrated that adherens junctions (AJs) are impaired in schwannoma cells because of a ubiquitous, upregulated Rac activity. However, the mechanism by which loss of contact inhibition leads to proliferation remains obscure in merlin-deficient tumors. In this study, we show that proliferative Wnt/β-catenin signaling is elevated as active β-catenin (dephosphorylated at serine 37 and threoine 41) localizes to the nucleus and the Wnt targets genes c-myc and cyclin D1 are upregulated in confluent human schwannoma cells. We demonstrate that Rac effector p21-activated kinase 2 (PAK2) is essential for the activation of Wnt/β-catenin signaling because depletion of PAK2 suppressed active β-catenin, c-myc, and cyclin D1. Most importantly, the link between the loss of the AJ complex and the increased proliferation in human schwannoma cells is connected by Src and platelet-derived growth factor receptor-induced tyrosine 654 phosphorylation on β-catenin and associated with degradation of N-cadherin. We also demonstrate that active merlin maintains β-catenin and N-cadherin complex at the plasma membrane through direct regulation. Finally, we demonstrate that phosphorylation of tyrosine 654 is critical for the increased proliferation in human schwannoma cells because overexpression of a Y654F mutant β-catenin reduces hyperproliferation of schwannoma cells. We suggest a model that these pathways are coordinated and relevant for proliferation in merlin-deficient tumors.
Original languageEnglish
Pages (from-to)1101-1112
Number of pages0
JournalNeoplasia
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Cadherins
  • Cell Membrane
  • Cell Proliferation
  • Contact Inhibition
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Models
  • Biological
  • Neurilemmoma
  • Neurofibromin 2
  • Phosphorylation
  • Protein Binding
  • RNA
  • Small Interfering
  • Receptors
  • Platelet-Derived Growth Factor
  • Wnt Proteins
  • Wnt Signaling Pathway
  • beta Catenin
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein
  • src Homology Domains
  • src-Family Kinases

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