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

    Authors

    C. Thaxton; J. Lopera; M. Bott;C. Fernandez-Valle

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abbreviated Journal Title

    Oncogene

    Keywords

    nerve; merlin; beta 1 integrin; ErbB2; Cdc42; SIGNAL-TRANSDUCTION; PERIPHERAL-NERVE; AUTOCRINE LOOP; GROWTH-FACTOR; MERLIN; PAXILLIN; ACTIVATION; RECEPTORS; LOCALIZATION; MYELINATION; Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &; Heredity

    Abstract

    Mutations in the neuro. bromatosis 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 b1 integrin, and by protein kinase A following neuregulin-1b (NRG1b) 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 b1 integrin antibody. Dual stimulation with laminin-1 and NRG1 beta 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 beta 1 integrins as potential therapeutic targets for NF2.

    Journal Title

    Oncogene

    Volume

    27

    Issue/Number

    19

    Publication Date

    1-1-2008

    Document Type

    Article

    Language

    English

    First Page

    2705

    Last Page

    2715

    WOS Identifier

    WOS:000255259500005

    ISSN

    0950-9232

    Share

    COinS