Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways

Oncogene. 2008 Apr 24;27(19):2705-15. doi: 10.1038/sj.onc.1210923. Epub 2007 Nov 12.

Abstract

Mutations in the neurofibromatosis type 2 (NF2) gene cause formation of schwannomas and other tumors in the nervous system. The NF2 protein, Schwannomin/Merlin, is a cytoskeleton-associated tumor suppressor regulated by phosphorylation at serine 518 (S518). Unphosphorylated Schwannomin restricts cell proliferation in part by inhibiting Rac- and p21-activated kinase (Pak). In a negative-feedback loop, Pak phosphorylates Schwannomin inactivating its ability to inhibit Pak. Little is known about receptor mechanisms that promote Pak activity and Schwannomin phosphorylation. Here we demonstrate in primary Schwann cells (SCs) that Schwannomin is rapidly phosphorylated on S518 by Pak following laminin-1 binding to beta1 integrin, and by protein kinase A following neuregulin-1beta (NRG1beta) binding to ErbB2/ErbB3 receptors. These receptors, together with phosphorylated Schwannomin, P-Pak, Cdc42 and paxillin are enriched at the distal tips of SC processes, and can be isolated as a complex using beta1 integrin antibody. Dual stimulation with laminin-1 and NRG1beta does not synergistically increase Schwannomin phosphorylation because ErbB2 kinase partially antagonizes integrin-dependent activation of Pak. These results identify two parallel, but interactive pathways that inactivate the tumor suppressor activity of Schwannomin to allow proliferation of subconfluent SCs. Moreover, they identify ErbB2, ErbB3 and beta1 integrins as potential therapeutic targets for NF2.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Membrane / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Laminin / physiology*
  • Neuregulin-1 / physiology*
  • Neurofibromin 2 / metabolism*
  • Phosphorylation
  • Rats
  • Schwann Cells / cytology
  • Schwann Cells / enzymology*
  • Schwann Cells / metabolism
  • Signal Transduction / physiology*
  • p21-Activated Kinases / physiology*

Substances

  • Laminin
  • Neuregulin-1
  • Neurofibromin 2
  • laminin 1
  • neuregulin beta
  • p21-Activated Kinases
  • Cyclic AMP-Dependent Protein Kinases