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

• Published in: Oncogene Vol. 27; no. 19; pp. 2705 - 2715
• Main Authors: Thaxton, C, Lopera, J, Bott, M, Fernandez-Valle, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-04-2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Animals, Newborn; Apoptosis; Biological and medical sciences; Care and treatment; Cdc42 protein; Cell Biology; Cell Membrane - metabolism; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - physiology; Cytoskeleton; ErbB-2 protein; ErbB-3 protein; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetic disorders; GTP-binding protein; Human Genetics; Integrins; Internal Medicine; Kinases; Laminin; Laminin - physiology; Medicine; Medicine & Public Health; Molecular and cellular biology; Nervous system; Neuregulin; Neuregulin-1 - physiology; Neurofibromatosis; Neurofibromatosis 2; Neurofibromin 2; Neurofibromin 2 - metabolism; Neurological disorders; Oncology; original-article; p21-activated kinase; p21-Activated Kinases - physiology; Paxillin; Phosphorylation; Phosphotransferases; Physiological aspects; Protein kinase A; Proteins; Rats; Receptor mechanisms; Schwann cells; Schwann Cells - cytology; Schwann Cells - enzymology; Schwann Cells - metabolism; Signal Transduction - physiology; Therapeutic targets; Tumor suppressor genes; Tumors; United States; β1 integrin; ErbB2; Merlin; nerve; Cdc42; Phosphorylation; Enzyme; Triphosphoric monoester hydrolases; Neuroglia; CDKN1A Gene; erbB2 Gene; dGTPase; Esterases; cAMP-dependent protein kinase; Carcinogenesis; Nerve; Integrin; Laminin; Schwann cell; C-Onc gene; Hydrolases; Neuregulin; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210923

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.