Title

Neuregulin And Laminin Stimulate Phosphorylation Of The Nf2 Tumor Suppressor In Schwann Cells By Distinct Protein Kinase A And P21-Activated Kinase-Dependent Pathways

Keywords

β1 integrin; Cdc42; ErbB2; M erlin; Nerve

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 β1 integrin, and by protein kinase A following neuregulin-1β (NRG1β) 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 β1 integrin antibody. Dual stimulation with laminin-1 and NRG1β 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 β1 integrins as potential therapeutic targets for NF2. © 2008 Nature Publishing Group All rights reserved.

Publication Date

4-24-2008

Publication Title

Oncogene

Volume

27

Issue

19

Number of Pages

2705-2715

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1038/sj.onc.1210923

Socpus ID

42549093636 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/42549093636

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