title: Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with neurofibromatosis Type 1 (NF1). These Schwann cell lineage-derived sarcomas aggressively invade adjacent nerve and soft tissue, frequently precluding surgical resection. Little is known regarding the mechanisms underlying this invasive behavior. We have shown that MPNSTs express neuregulin-1 (NRG-1) beta isoforms, which promote Schwann cell migration during development, and NRG-1 alpha isoforms, whose effects on Schwann cells are poorly understood. Hypothesizing that NRG-1 beta and/or NRG-1 alpha promote MPNST invasion, we found that NRG-1 beta promoted MPNST migration in a substrate-specific manner, markedly enhancing migration on laminin but not on collagen type I or fibronectin. The NRG-1 receptors erbB3 and erbB4 were present in MPNST invadopodia (processes mediating invasion), partially colocalized with focal adhesion kinase and the laminin receptor beta(1)-integrin and coimmunoprecipitated with beta(1)-integrin. NRG-1 beta stimulated human and murine MPNST cell migration and invasion in a concentration-dependent manner in three-dimensional migration assays, acting as a chemotactic factor. Both baseline and NRG-1 beta-induced migration were erbB-dependent and required the action of MEK 1/2, SAPK/JNK, PI-3 kinase, Src family kinases and ROCK-I/II. In contrast, NRG-1 alpha had no effect on the migration and invasion of some MPNST lines and inhibited the migration of others. While NRG-1 beta potently and persistently activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG-1 alpha did not activate Akt and activated these other kinases with kinetics distinct from those evident in NRG-1 beta-stimulated cells. These findings suggest that NRG-1 beta enhances MPNST migration and that NRG-1 beta and NRG-1 alpha differentially modulate this process.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
authors.forename: Jenell M
authors.initials: JM
authors.lastname: Eckert
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Byer
authors.forename: Buffie J
authors.initials: BJ
authors.lastname: Clodfelder-Miller
authors.forename: Steven L
authors.initials: SL
authors.lastname: Carroll
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007700:Kinetics; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018317:Nerve Sheath Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D020890:Neuregulin-1 / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4; D012583:Schwann Cells / Q000502:physiology
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D019012:Integrin beta1; D007797:Laminin; C094131:NRG1 protein, human; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D020033:Protein Isoforms; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4